Genetic/Genomic Testing and Pharmacogenetics (Policy OCA

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Medical Policy and InterQual® Criteria

Genetic/Genomic Testing and Pharmacogenetics

Policy Number: OCA 3.727 Version Number: 39 Version Effective Date: 07/01/21

Product Applicability All Plan+ Products

Well Sense Health Plan Boston Medical Center HealthNet Plan Well Sense Health Plan MassHealth Qualified Health Plans/ConnectorCare/Employer Choice Direct Senior Care Options ◊

Notes: + Disclaimer and audit information is located at the end of this document. ◊ The guidelines included in this Plan policy are applicable to members enrolled in Senior Care Options only if there are no criteria established for the specified service in a Centers for Medicare & Medicaid Services (CMS) national coverage determination (NCD) or local coverage determination (LCD) on the date of the prior authorization request. Review the member’s product-specific benefit documents at www.SeniorsGetMore.org to determine coverage guidelines for Senior Care Options.

Policy Summary The Plan considers genetic and genomic testing to be medically necessary for the diagnosis of genetic disease in children and adults, for the determination of future risk of a suspected disease, for the prediction of drug responses, and/or for the detection of risks of specific diseases to future children when the Plan’s applicable medical policy criteria are met or Plan-adopted InterQual® criteria are met based on the requested genetic test (with InterQual® criteria utilized when criteria are not included in a Plan medical policy). Prior authorization is required. The Plan’s prior authorization requirements are based on the type of genetic test requested, indication(s) for testing, and if the test is ordered, administered, and processed by participating providers and participating laboratories (or non-

Genetic/Genomic Testing and Pharmacogenetics

+ Plan refers to Boston Medical Center Health Plan, Inc. and its affiliates and subsidiaries offering health coverage plans to enrolled members. The Plan operates in Massachusetts under the trade name Boston Medical Center HealthNet Plan and in other states under the trade name Well Sense Health Plan. 1 of 111

participating providers and non-participating laboratories). Review the Plan’s Preimplantation Genetic Testing medical policy, policy number OCA 3.726, rather than InterQual® criteria for medical guidelines for preimplantation genetic testing; preimplantation genetic testing is a covered service for some BMC HealthNet Plan members, as specified in the member’s applicable benefit document available at www.bmchp.org.

Genetic and genomic testing must comply with applicable Plan reimbursement policies and redirection guidelines. For genetic tests ordered, administered, and processed by participating providers and participating laboratories, Plan prior authorization is required for all molecular and chromosomal genetic testing EXCEPT for a limited number of prenatal genetic screening tests when billed with one (1) of the ICD-10 primary pregnancy diagnosis codes listed in either Category 1 (i.e., procedure codes with the prior authorization requirement waived for members with a Plan-specified, routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis code) or Category 2 (i.e., procedure codes with the prior authorization requirement waived for members with a Plan-specified, high-risk pregnancy ICD-10 primary diagnosis code) of the Applicable Coding section of this policy and when the Plan’s applicable medical policy criteria are met or Plan-adopted InterQual® criteria are met (based on the requested testing). The ICD-10 primary pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options members. Prior authorization is REQUIRED for genetic testing for a pregnant member when the applicable procedure code is NOT listed in Category 1 or Category 2 of the Applicable Coding section. Prior authorization is REQUIRED for ALL molecular and chromosomal genetic testing (when testing is NOT provided to a pregnant member).

When genetic tests are order, administered, and/or processed by non-participating providers and/or non-participating laboratories (NOT contracted with the Plan), prior authorization is REQUIRED for all genetic testing, including prenatal genetic screening tests; the list of primary diagnosis codes waived from the prior authorization process would NOT apply to non-participating providers and non- participating laboratories. Biochemical genetic tests used to study molecular markers such as the amount or activity level of proteins and/or steroids to indicate changes to DNA or as biomarkers to determine disease progression, tumor behavior, risk of cancer recurrence, and/or diagnose or treat a genetic condition require prior authorization when specified in the Plan’s Code Look-Up Tools, Prior Authorization Matrix, or a Plan medical policy available at www.bmchp.org for services provided to BMC HealthNet Plan members (including Senior Care Options members) and at www.wellsense.org for testing requested for Well Sense Health Plan members.

The Plan recommends that adequate pre-test genetic counseling (including but not limited to preparing the member for possible outcomes of testing including positive results) and post-test genetic counseling be provided by a health care professional with expertise in genetics for all genetic testing conducted with Plan members. Genetic counseling provided to a Plan member (and/or guardian if the member is under the age of 18) should be documented in the member’s medical record and conducted by an appropriately trained practitioner with expertise and experience in genetics, including a provider acting within the scope of the practitioner’s license and practice, clinical geneticist, or genetic counselor.

Genetic/Genomic Testing and Pharmacogenetics

The Plan complies with coverage guidelines for all applicable state-mandated benefits and federally- mandated benefits that are medically necessary for the member’s condition. It will be determined during the prior authorization process if the genetic test is considered medically necessary or experimental and investigational for the requested indication. The Plan’s Medically Necessary medical policy, policy number OCA 3.14, indicates the product-specific definitions of medically necessary treatment, and the Plan’s Experimental and Investigational Treatment medical policy, policy number OCA 3.12, includes the product-specific definitions of experimental or investigational treatment. Plan- adopted InterQual® criteria and the following medical policies include additional prior authorization guidelines for genetic testing and related services:

1. Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573, includes guidelines for chromosomal microarray analysis (CMA) when used for the diagnosis of an adult or pediatric member with unexplained intellectual disability, developmental delay, symptoms or findings consistent with an autism spectrum disorder, and/or multiple congenital anomalies; applicable InterQual® criteria must be met for CMA for this indication. The Applicable Coding section of policy number OCA 3.573 includes the Plan’s list of high-risk primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization for CMA when testing is used for prenatal genetic screening or other pregnancy-related indications such as fetal demise or stillbirth.

When CMA is requested to establish a diagnosis and/or prognosis for a member with a malignancy (testing also known as cytogenomic neoplastia microarray analysis) or any other indication not specified above, InterQual® criteria must be met for the requested indication. If no InterQual® criteria are available for the specified indication for CMA testing, applicable medical necessity criteria and coding guidelines must be met in the Medical Policy Statement, Limitations, and Applicable Coding sections of this Genetics/Genomic Testing and Pharmacogenetics medical policy and Plan Medical Director review is required for individual consideration.

2. Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances medical policies, policy number OCA 3.98 for BMC HealthNet members and policy number OCA 3.99 for Well Sense Health Plan members, include guidelines related to specimen validity testing using DNA authentication in conjunction with drug testing for Plan members.

3. Genetic Testing for Fragile X-Associated Disorders medical policy, policy number OCA 3.571, includes the list of primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization; applicable InterQual® criteria are used to determine the medical necessity of requested testing.

4. Genetic Testing for Hereditary Thrombophilia medical policy, policy number OCA 3.728, includes the clinical review criteria used to determine medical necessity of requested testing.

Genetic/Genomic Testing and Pharmacogenetics

5. Preimplantation Genetic Testing medical policy, policy number OCA 3.726, specifies the clinical review criteria used to determine medical necessity of requested testing ONLY when preimplantation genetic testing is a covered service for a Plan member.

Description of Item or Service Genetic Testing/Genomic Testing: Genetic tests identify changes in chromosomes, genes, and/or proteins to provide information about an individual’s genetic predisposition to certain inherited conditions, diagnosis, carrier status, identification or relationships, and/or expected interaction with therapeutic drugs. Methods of testing include molecular genetic tests (or gene tests) to study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder, chromosomal genetic tests to analyze whole chromosomes or long lengths of DNA to see if there are large genetic changes that cause a genetic condition, and/or biochemical genetic tests to study molecular markers such as the amount or activity level of proteins and/or steroids to indicate changes to DNA or as biomarkers to determine disease progression, tumor behavior, risk of cancer recurrence, and/or diagnose or treat a genetic disorder. Genomics is the study of genes and their functions to develop effective and safe pharmacological treatments tailored to an individual’s genetic makeup. Types of genetic/genomic testing may include:

1. Carrier: Genetic testing that identifies the presence of a carrier state. This type of test is offered to individuals who have a family history of a genetic disorder and to individuals in certain ethnic groups which have an increased risk of specific genetic conditions. Testing both parents provides information about a couple’s risk of having a child with a genetic condition.

2. Diagnostic: Genetic testing that confirms or rules out the presence of a specific genetic chromosomal abnormality. Diagnostic testing can be performed before birth or at any time during a person’s life, but diagnostic testing is not available for all genes or for all genetic conditions. This type of test commonly detects a specific gene alteration but is often not able to determine disease severity or age of onset. Diagnostic test results can influence medical management.

3. Forensic: Genetic testing that uses DNA sequences to identify an individual for legal purposes. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, and/or establish biological relationships between people (e.g., paternity). Forensic genetic testing may also include specimen validity testing using DNA authentication in conjunction with drug testing.

4. Newborn Screening: According to the American Academy of Pediatrics in 2009, the purpose of newborn screening for genetic disorders is to limit the morbidity and mortality attributable to selected inherited diseases. Testing is normally done early infancy to detect conditions for which early intervention can avoid serious health issues or even death.

Genetic/Genomic Testing and Pharmacogenetics

5. Pharmacogenetics/Pharmacogenomics: Genetic and genomic testing is used to evaluate the interaction between genetics and therapeutic drugs and classify subtle variations in an individual's genetic makeup to determine whether a drug is suitable for a particular patient, and if so, what would be the safest and most effective dose. Pharmacogenomics refers to the general study of the many different genes that determine drug behavior, evaluating genetic differences within a population that explain certain observed responses to a drug susceptibility to a health problem. Pharmacogenetics refers to the study of inherited differences (variation) in drug metabolism and response, evaluating individual genetic factors that influence how a drug works and analyzing unexpected drug responses to determine a genetic case. The distinction between the two terms, pharmacogenetics and pharmacogenomics, has become somewhat arbitrary in the scientific literature, and they have been used interchangeably.

6. Predictive: Genetic testing to determine whether an individual has an increased risk for a particular disease by detecting genetic mutations associated with disorders that have not yet manifested or produced symptoms. Results from this type of test are usually expressed in terms of probability and are therefore less definitive since disease susceptibility may also be influenced by other genetic and non-genetic (e.g. environmental, lifestyle) factors. This type of testing can help individuals who have a family member with a genetic disorder, but have no features of the disorder at the time of testing. Predictive testing results can provide information about an individual’s risk of developing a specific disorder and help with making decisions about medical care.

7. Prenatal: Genetic testing that detects changes in fetal genes or chromosomes. This type of testing is done during pregnancy when a fetus has an increased risk for a genetic or chromosomal disorder.

8. Whole Genome Sequencing and Whole Exome Sequencing: Genetic testing that examines the entire genome or exome to discover genetic alterations that may be the cause of disease. Currently, this type of test may be used in complex diagnostic cases but is considered experimental and investigational by the Plan (as specified in the Limitations section of this policy). Whole genome sequencing and whole exome sequencing are being explored for use in asymptomatic individuals to predict future disease.

Medical Policy Statement For genetic tests ordered, administered, and processed by participating providers and participating laboratories, Plan prior authorization is required for all molecular and chromosomal genetic testing except for prenatal genetic screening tests for a member with one (1) of the primary pregnancy diagnosis codes specified in the Applicable Coding section of this policy when applicable medical necessity criteria are met. The primary pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options members. When genetic tests are order, administered, and processed by non-participating providers and/or non-participating laboratories (NOT contracted with the Plan), prior authorization is required for all genetic testing, including prenatal Genetic/Genomic Testing and Pharmacogenetics

genetic screening tests; the list of primary diagnosis codes waived from the prior authorization process would NOT apply to non-participating providers and non-participating laboratories. Biochemical genetic tests used to study molecular markers such as the amount or activity level of proteins and/or steroids to indicate changes to DNA or as biomarkers to determine disease progression, tumor behavior, risk of cancer recurrence, and/or diagnose or treat a genetic condition require prior authorization when specified in the Plan’s Code Look-Up Tools, Prior Authorization Matrix, or a Plan medical policy available at www.bmchp.org for services provided to BMC HealthNet Plan members (including Senior Care Options members) and at www.wellsense.org for testing requested for Well Sense Health Plan members. See section A below for criteria for genetic testing that requires Plan prior authorization. Review section B below for criteria for genetic testing that does not require Plan authorization. The Summary section of this policy includes a listing of additional Plan medical policies related to genetic testing.

A. Prior authorization is REQUIRED when the member is NOT pregnant and/or when the genetic test is ordered, administered, and/or processed by a non-participating provider and/or non- participating laboratory for a pregnant member. Medical necessity criteria must be met in a Plan medical policy or Plan-adopted InterQual® criteria (with InterQual® criteria utilized when applicable criteria are not included in a Plan medical policy) for the requested genetic test. At least ONE (1) of the following criteria must be met, as specified below in items 1 through 3:

1. Carrier Screening for Members Considering Pregnancy:

The following applicable medical necessity criteria must be met (rather than InterQual® criteria) for cystic fibrosis carrier (CF) screening, spinal muscular atrophy (SMA) carrier screening, or BOTH types of carrier screening when a member is considering pregnancy, as specified below in item a (for CF carrier screening), item b (for SMA carrier screening), or criteria in BOTH items a and b are met (when CF and SMA carrier screening are requested):

a. Cystic Fibrosis (CF) Carrier Screening:

ALL of the following criteria must be met (rather than InterQual® criteria) for medically necessary CF carrier testing, as specified below in items (1) through (3):

(1) The member has no prior results for CF screening; AND

(2) Member has undergone pretest genetic counseling; AND

(3) ONE (1) of the following applicable criteria must be met for the Plan member, as specified below in item (a) or (b):

(a) CF carrier screening will be conducted on an adult female member/adult member with female reproductive organs (age 18 or older on the date of service) considering pregnancy; OR Genetic/Genomic Testing and Pharmacogenetics

(b) CF carrier screening will be conducted on an adult male member/adult member with male reproductive organs (age 18 or older on the date of service) when BOTH of the following guidelines are met, as specified below in item i and item ii:

i. The adult male member/adult member with male reproductive organs is considering pregnancy with a female partner/partner with female reproductive organs; AND

ii. The results of the CF screening test of the member’s female partner/individual with female reproductive organs is positive, and CF screening of the adult male member/adult member with male reproductive organs is medically necessary to determine carrier status; ≈ AND/OR

≈ Note: When the results of the CF screening test of the member’s female partner/partner with female reproductive organs are negative, screening of the male partner is NOT medically necessary for CF.

b. Spinal Muscular Atrophy (SMA) Carrier Screening:

ALL of the following criteria must be met (rather than InterQual® criteria) for medically necessary testing, as specified below in items (1) through (3):

(1) The member has no prior results for SMA screening; AND

(2) Member has undergone pretest genetic counseling; AND

(3) ONE (1) of the following applicable criteria must be met for the Plan member, as specified below in item (a) or (b):

(a) SMA carrier screening will be conducted on an adult female member/adult member with female reproductive organs (age 18 or older on the date of service) considering pregnancy; OR

(b) SMA carrier screening will be conducted on an adult male member/adult member with male reproductive organs (age 18 or older on the date of service) when BOTH of the following guidelines are met, as specified below in item i and item ii:

i. The adult male member/adult member with male reproductive organs is considering pregnancy with a female partner/partner with female reproductive organs; AND

Genetic/Genomic Testing and Pharmacogenetics

ii. The results of the SMA screening test of the member’s female partner/individual with female reproductive organs is positive, and SMA screening of the adult male member/adult member with male reproductive organs is medically necessary to determine carrier status; ≈ OR

≈ Note: When the results of the SMA screening test of the member’s female partner/partner with female reproductive organs are negative, screening of the male partner is NOT medically necessary for SMA.

2. Thyroid Nodule Genetic Testing with Afirma Thyroid FNA Analysis/Afirma Genetic Sequence Classifier(GSC)/Afirma Malignancy Classifiers (which include the Afirma BRAF and Afirma Medullary Thyroid Cancer MTC as a component of the Afirma GSC to help guide surgical decisions) or ThyroSeq Genomic Classifier (GC)/ThyroSeq v3:

ONE (1) or more of the following applicable criteria must be met for the Plan member, as specified below in item a (for genetic testing to diagnose indeterminate thyroid nodules), item b (for BRAF V600E testing to diagnose and/or assess the prognosis of papillary thyroid carcinoma), or criteria in BOTH items a and b are met (when genetic testing is requested to predict whether indeterminate thyroid nodules are malignant and BRAF v600E testing is a component of the thyroid nodule genetic testing):

a. Diagnosis of Indeterminate Thyroid Nodules:

Thyroid nodule genetic testing is conducted on FNA samples to predict whether indeterminate thyroid nodules are malignant. Better identification of benign nodules should prevent unnecessary surgeries. Tests include proprietary commercial products such as Afirma Thyroid FNA Analysis/Afirma GSC (Veracyte, Inc.) or ThyroSeq GC/ThyroSeq v3 (University of Pittsburgh Medical Center, CBLPath, Inc.). The Plan considers genetic testing of indeterminate thyroid nodules to be medically necessary to aid in the diagnosis of indeterminate thyroid nodules when ALL of the following Plan criteria are met (rather than utilizing InterQual® criteria), as specified below in items (1) through (3):

(1) The test results will affect the decision for surgery and the member’s treatment plan; AND

(2) Only one (1) of these tests will be performed (either Afirma Thyroid FNA Analysis/Afirma GSC or ThyroSeq GC/ThyroSeq v3); AND

(3) Testing will occur NO MORE THAN once per member per episode of care; AND/OR

Genetic/Genomic Testing and Pharmacogenetics

b. Genetic Testing to Diagnose Papillary Thyroid Carcinoma:

The following applicable criteria must be met for the Plan member, as specified below in item (1) or (2):

(1) BRAF p.Val600Glu (V600E) Testing to Diagnose Papillary Thyroid Carcinoma:

Thyroid nodule genetic testing includes next-generation sequencing of specific genes (e.g., BRAF v600E) that are associated with thyroid malignancy. BRAF v600E testing to diagnose papillary thyroid carcinoma (PTC) or to assess the member’s prognosis after diagnosed with PTC is included in the Afirma Thyroid FNA Analysis/Afirma GSC (Veracyte, Inc.) and the ThyroSeq GC/ThyroSeq v3 (University of Pittsburgh Medical Center, CBLPath, Inc.). The Afirma BRAF testing is conducted in conjunction with either an Afirma FNA or GSC for indeterminate or malignant results and will not be reimbursed separately unless specified otherwise in the Applicable Coding section of this policy. The Afirma Malignancy Classifier (MTC) may be performed as a component of the Afirma GSC and will not be reimbursed separately unless specified otherwise in the Applicable Coding section of this policy.

Review the Limitations section of this policy for clinical guidelines for other types of genetic tests used to classify indeterminate thyroid nodules as benign or malignant, SEPARATE BRAF p.Val600Glu (V600E) testing for members with indeterminate thyroid fine-needle aspiration biopsy cytology; i.e., BRAF V000E testing that is NOT a component of the ThyroSeq GC/ThyroSeq v3 or Afirma Thyroid FNA Analysis/Afirma GSC, and/or requests for Afirma Thyroid FNA Analysis/Afirma GSC or ThyroSeq GC/ThyroSeq v3 testing MORE FREQUENTLY than once per member per episode of care.

BRAF V600E testing is considered medically necessary as a COMPONENT of one of these tests when Plan criteria are met (rather than utilizing InterQual® criteria), as specified below in items (a) through (c):

(a) The test results will affect the member’s treatment plan; AND

(b) Only one (1) of these tests will be performed (either Afirma Thyroid FNA Analysis/Afirma GSC or ThyroSeq Genomic Classifier (GC)/ThyroSeq v3); AND

Genetic/Genomic Testing and Pharmacogenetics

(2) Afirma Xpression Atlas (XA):

The Afirma XA is an RNA sequencing-based test designed to analyze 761 variants and 130 fusions that have been linked to thyroid cancer (analyzing DNA, RNA, and gene products). This testing is performed on nodules that are suspicious for malignancy. Review the Limitations section of this policy for Plan guidelines; this test is considered experimental and investigational.

3. Additional Diagnostic and Targeted Genetic Testing or Pharmacogenetic Testing by Medical Condition:

a. The Plan considers targeted genetic testing to be medically necessary when BOTH of the following criteria are met, as specified below in item (1) and item (2):

(1) The results of the test will be clinically useful to the medical management of the member (e.g., confirm diagnosis to establish appropriate treatment plan or predict response to drug therapy); AND

(2) Applicable medical necessity criteria must be met in a Plan medical policy or Plan- adopted InterQual® criteria (with InterQual® criteria utilized when criteria are not included in a Plan medical policy); AND

b. When medical necessity criteria are NOT met for genetic testing in a Plan medical policy or Plan-adopted InterQual® criteria (with InterQual® criteria utilized when criteria are not included in a Plan medical policy), Plan Medical Director review is REQUIRED and BOTH of the following medical necessity criteria must be met and documented in the member’s medical record, as specified below in item (1) and item (2):

(1) General Guidelines for ALL Genetic Testing That Requires Plan Medical Director Review:

The Plan considers genetic testing medically necessary when ALL of the following applicable criteria are met and documented in the member’s medical record and the testing is approved by a Plan Medical Director, as specified below in items (a) through (e):

(a) The test is to be used for the diagnosis or determination of risk for a suspected disease for a member who meets ONE (1) of the following criteria, as specified below in item i or item ii:

i. Symptomatic (e.g., exhibiting signs and symptoms of a disease), known as diagnostic testing; OR

Genetic/Genomic Testing and Pharmacogenetics

ii. Pre-symptomatic, but at an increased risk of disease, as determined by current scientific literature which may be due to family history, ethnicity, or gender, known as predictive testing; AND

(b) The results of the test will be clinically useful to the medical management of the member (i.e., initiate a new course of therapy, alter an existing therapy, and/or determine prognosis or a level of surveillance); AND

(c) A treating provider in the appropriate field who is acting within the scope of the practitioner’s license and practice or a provider with genetic-counseling expertise (including clinical geneticist or genetic counselor) provides documentation (including a letter of medical necessity) supporting the recommendation for testing after reviewing risk factors, clinical scenarios, and family history; AND

(d) The testing is the only and/or most medically appropriate option available to obtain the necessary information to evaluate and treat the member; AND

(e) There is a sufficient amount of evidence in the scientific literature to support the validity and predictive accuracy of the test for the specified indication; AND

c. ONE (1) of the following applicable criteria must be met when Plan Medical Director review is required for genetic testing, as specified below EITHER item (1) or item (2) for each requested test:

(1) Criteria for Targeted Genetic Testing When Indication Not Specified as Medically Necessary in Plan-Adopted InterQual® Criteria or a Plan Medical Policy:

When the indication for genetic testing is NOT specified in Plan-adopted InterQual® criteria or a Plan medical policy (or applicable medical necessity criteria are NOT met), Plan Medical Director approval is required and the following medical record documentation must be submitted to the Plan by the treating provider, as specified below in items (a) through (e):

(a) Previous testing performed and/or alternatives available to obtain the information; AND

(b) Documentation that the member is experiencing signs and symptoms of a disease or that the member is pre-symptomatic and at an increased risk of developing the disease; AND

Genetic/Genomic Testing and Pharmacogenetics

(c) How the results of the test will be clinically useful either diagnostically, therapeutically, prognostically, and/or preventively; AND

(d) Name of provider who completed the member’s pre-test genetic counseling, date of counseling, and provider’s plan for post-test counseling (but this information is NOT required when testing is only for prediction of drug responses); AND

(e) Where the specific genetic test will be done and who will interpret the results; OR

(2) Criteria for Multigene Panel Testing (Rather than Targeted Genetic Testing) When Plan-Adopted InterQual® Criteria are Not Met or Not Available:

The use of a multigene testing panel may be considered medically necessary in addition to, or as an alternative to, disease-specific, targeted genetic testing (including the identification of susceptibility to hereditary cancer syndromes) when Plan-adopted InterQual® criteria are met. If the treating provider is recommending multigene panel testing rather than, or in addition to, condition-targeted genetic testing and Plan- adopted InterQual® criteria are NOT met, Plan Medical Director review is required. For Plan Medical Director review, medical record documentation must be submitted to the Plan with the prior authorization request demonstrating that ALL of the following criteria are met, as specified below in items (a) through (g):

(a) A recommendation for multigene panel testing for the member by an independent board-certified or board-eligible Medical Geneticist, an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic Counselor not employed by a commercial genetic testing laboratory, or a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory; this provider has a documented evaluation of the member which includes a completed 3-generation pedigree and intends to engage in post-test follow-up counseling; AND

(b) Member meets criteria for genetic testing outlined in item A1 above (General Genetic Testing Guidelines for ALL Testing) of this Medical Policy Statement section; AND

(c) All genes included in the multigene panel are relevant to the personal medical history, biological family medical history, and/or treatment plan for the member being tested and there are professional society management guidelines or Genetic/Genomic Testing and Pharmacogenetics

National Comprehensive National Comprehensive Cancer Network (NCCN) guidelines documenting the clinical utility of testing for the members who test positive for any and all genes in the panel (with these applicable references provided with the prior authorization request); AND

(d) The results of the requested multigene panel will directly impact the treatment plan and clinical decision-making process for the member being tested; AND

(e) There are no other known causative circumstances or factors (e.g., environmental exposures, injury, infection) that can explain the member’s symptoms or medical condition; AND

(f) Multigene panel testing is more practical testing to diagnose the member’s condition than the separate single gene tests or targeted panels that would be recommended (with supporting documentation provided); AND

(g) The member’s clinical presentation does not fit a well-described syndrome for which single-gene testing, targeted panel testing, or chromosomal microarray analysis is currently available for the member’s condition or is not clinically appropriate for the member (with supporting clinical documentation provided).

B. Prior authorization is NOT required for genetic screening for a pregnant member/member’s fetus when ALL of the following criteria are met, as specified below in items 1 through 3:

1. The pregnant member’s claim for the genetic screening test is submitted to the Plan with the following codes documented on the claim, as specified in the Applicable Coding section of this policy and included below in BOTH item a and item b:

a. The appropriate procedure code(s) for the genetic testing are listed in either Category 1 (i.e., procedure codes with the prior authorization requirement waived for members with a Plan-specified, routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis code) or Category 2 (i.e., procedure codes with the prior authorization requirement waived for members with a Plan-specified, high-risk pregnancy ICD-10 primary diagnosis code) of the Applicable Coding section of this policy; ◊ AND

b. One (1) of the Plan-specified, pregnancy ICD-10 diagnosis codes (for either a routine pregnancy or high-risk pregnancy) specified in the Applicable Coding section of this policy is listed as the primary diagnosis for the member and prior authorization is waived for the applicable genetic testing procedure code(s) for that primary pregnancy diagnosis code; ◊ AND

2. The genetic test is ordered, administered, and processed by a participating provider and a participating laboratory; AND Genetic/Genomic Testing and Pharmacogenetics

3. There is medical record documentation of medical necessity for the genetic screening test(s) for the pregnant member (for both population-based screening and targeted population-based screening) and InterQual® criteria are met (which the Plan may validate with medical record audit rather than through the prior authorization process). ◊

◊ Notes:

• Medical Record Documentation: The member’s medical record must document the medical necessity of testing (RATHER than requiring prior authorization), as stated in applicable InterQual® criteria for genetic testing for the requested indication(s).

• Genetic Screening for a Pregnant Member/Member’s Fetus: There are a limited number of genetic testing procedure codes that do NOT require prior authorization when billed with EITHER Plan-specified, routine pregnancy ICD-10 primary diagnosis codes (listed in Category 1) or high-risk pregnancy ICD-10 primary diagnosis codes (listed in Category 1 or Category 2) in the Applicable Coding section. The ICD-10 primary pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options members. Prior authorization is REQUIRED for genetic testing of a pregnant member when the applicable procedure code is NOT listed in Category 1 or Category 2 of the Applicable Coding section.

• Genetic Testing for All Members: All genetic testing procedure codes NOT listed in Category 1 or Category 2 of the Applicable Coding section of this policy REQUIRE prior authorization for ALL Plan members, including but not limited to procedure codes listed in Category 3 (i.e., procedure codes that require prior authorization for all diagnosis codes) or Category 4 (i.e., codes considered experimental and investigational for all diagnosis codes).

• Other Applicable Medical Policies: See separate Plan guidelines, including clinical criteria and corresponding ICD-10 primary pregnancy diagnosis codes that do NOT require Plan authorization, for genetic testing for fragile X-associated disorders (for known carriers and individuals at risk) in the Plan’s Genetic Testing for Fragile X-Associated Disorders medical policy, policy number OCA 3.571, and the Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573, for genetic testing for unexplained intellectual disabilities and/or multiple congenital anomalies.

Genetic/Genomic Testing and Pharmacogenetics

Limitations The following the limitations apply to ALL Plan products, as specified below in items 1 through 13:

1. Forensic genetic testing is NOT covered.

2. Genetic Testing to Confirm the Identity of Laboratory Specimens:

The Plan considers genetic testing to confirm the identity of a laboratory specimen (e.g., know error® DNA Specimen Provenance Assay or ToxProtect™ DNA-verified Urine Drug Test) to NOT be medically necessary. The know error® system/ know error® DNA Specimen Provenance Assay/DSPA (Strand Diagnostics LLC) utilizes bar coding, forensic principles, and DSPA testing to confirm that surgical biopsy samples being evaluated belong exclusively to the patient being diagnosed and further confirm tissue specimens are free from contamination. The Plan considers confirmation testing of a specimen to be a component of routine laboratory/pathology quality control and is therefore considered provider liability.

The ToxProtect™ DNA-verified Urine Drug Test (Genotox Laboratories) is used to verify the identity of urine specimens for drug screening. Confirmation testing of a specimen (as a component of drug testing for any type of specimen collected, any drug class/classes, and for any indication) is an element of routine laboratory/pathology quality control and therefore is considered the provider’s liability. For BMC HealthNet Plan members, review the Plan’s Drug Screening/Testing (DS/T): Drugs of Abuse reimbursement policy, policy number 4.94, and the Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances medical policy, policy number OCA 3.98, available at www.bmchp.org. For Well Sense Health Plan members, see the Plan’s Drug Screening/Testing (DS/T): Drugs of Abuse reimbursement policy, policy number 4.94, and the Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances medical policy, policy number OCA 3.99.

3. Genetic testing that is marketed directly to consumers (direct-to-consumer or DTC) that is ordered by a member without the order of a treating health care provider is NOT covered.

4. Unless specified otherwise in InterQual® criteria or in an applicable Plan medical policy, the Plan does NOT cover genetic testing for members less than age 18 on the date of service because it is considered investigational and there are no recommended preventive interventions for this age group. Plan Medical Director review is required for individual consideration. The National Society of Genetic Counselors (NSGC) “encourages deferring predictive genetic testing of minors for adult-onset conditions when results will not impact childhood medical management or significantly benefit the child.”

Genetic/Genomic Testing and Pharmacogenetics

5. Endometrial Receptivity Genetic Testing:

Review the Plan’s Infertility Services medical policy, policy number OCA 3.725 for medical necessity guidelines related to gene profiling to estimate the receptivity of the endometrium for embryo transfer and implantation during ART (e.g., Endometrial Receptivity Analysis by Igenomix).

6. Liquid Biopsy Testing Using Circulating Cell Free DNA or Circulating Tumor Cells:

Liquid biopsy tests, i.e., circulating cell free DNA or circulating tumor cells tests (CTC), (e.g., ColonSentry by Stage Zero Life Sciences, Epi proColon by Epigenomics Inc., Guardant360 by Guardant Health, OncoCEE CTC by Biocept) for any indication, including but NOT limited to the screening of breast cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, or prostate cancer, are considered either experimental and investigational or NOT medically necessary unless InteQual® clinical review criteria are met for the specific test and requested indication (if/when applicable InterQual® criteria are established).

7. Multigene Panel Testing:

The Plan considers the clinical utility of multigene panel testing for prenatal diagnosis, preimplantation testing of an embryo, and/or when used in the general population to be experimental and investigational or NOT medically necessary. For other indications, review the applicable Plan-adopted InterQual® criteria and the medical necessity criteria in the Medical Policy Statement section of this policy for multigene panel testing.

8. Predictive Algorithm/Classifier:

When NOT specified as medically necessary according to Plan-adopted InterQual® criteria or a Plan medical policy, Plan Medical Director approval is required for the use of microRNA profiling and/or gene expression testing (i.e., testing for genetic alterations related to malignancy with analysis of messenger RNA/mRNA) utilizing fine-needle aspirate or tissue with a predictive algorithm/classifier. Gene expression testing may be used to evaluate genetic variants to assess the risk of tissue as either benign or malignant when the presence of cancer cannot be ruled out by cytology. Examples of these tests include but are not limited to the following: OncoTarget/OncoTreat (Columbia University/Darwin Health); ThyraMIR (Interpace Diagnostics) used in combination with ThyGeNEXT, formerly called ThyGenX, (Interpace Diagnostics); Afirma Gene Sequencing Classifier (GSC) (Veracyte, Inc.); ThyroSeq v0; ThyroSeq v1; and ThyroSeq v2 (University of Pittsburg Medical Center, CBLPath, Inc.).

See the Medical Policy Statement section of this policy for medical necessity guidelines related to the use of EITHER Afirma Thyroid FNA Analysis/Afirma Genetic Sequence Classifier (GSC) (Veracyte, Inc.) OR ThyroSeq Genomic Classifier (GC)/ThyroSeq v3 (University of Pittsburgh Medical Center, CBLPath, Inc.) to classify indeterminate nodules as benign or malignant (with Genetic/Genomic Testing and Pharmacogenetics

only one of these tests performed no more than once per member per episode of care determined to be medically necessary).

9. Thrombophilia Genetic Testing:

See the Plan’s Genetic Testing for Hereditary Thrombophilia medical policy, policy number OCA 3.728, rather than this policy for prior authorization guidelines and limitations related to genetic testing to diagnose hereditary thrombophilia.

10. Thyroid Cancer Testing or Diagnosis of Indeterminate Nodules:

a. Plan Medical Director review is required for individual consideration for SEPARATE BRAF p.Val600Glu (V600E) testing for members with indeterminate thyroid fine-needle aspiration biopsy cytology to DIAGNOSE papillary thyroid carcinoma (PTC).

BRAF v600E testing to diagnose PTC is included in the Afirma Thyroid FNA Analysis/Afirma Genetic Sequence Classifier (GSC) (Veracyte, Inc.) and the ThyroSeq Genomic Classifier (GC)/ThyroSeq v3 (University of Pittsburgh Medical Center, CBLPath, Inc.). BRAF V600E testing is considered medically necessary as a COMPONENT of one of these tests when applicable Plan criteria are met for the use of EITHER Afirma Thyroid FNA Analysis/Afirma GSC OR ThyroSeq GC/ThyroSeq v3 (with only one of these tests performed NO MORE THAN once per member per episode of care determined to be medically necessary), as specified in the Medical Policy Statement section of this policy.

b. Plan Medical Director review is required for individual consideration for SEPARATE BRAF p.Val600Glu (V600E) testing for members diagnosed with PTC for assessment of the member’s PROGNOSIS.

BRAF v600E testing to assess the member’s prognosis after diagnosed with PTC is included in the Afirma Thyroid FNA Analysis/Afirma GSC and the ThyroSeq GC/ThyroSeq v3. BRAF V600E testing is considered medically necessary as a COMPONENT of one of these tests when applicable Plan criteria are met for the use of EITHER Afirma Thyroid FNA Analysis/Afirma GSC OR ThyroSeq GC/ThyroSeq v3 (with only one of these tests performed NO MORE THAN once per member per episode of care determined to be medically necessary), as specified in the Medical Policy Statement section of this policy.

c. Plan Medical Director review is required for the use of Afirma Thyroid FNA Analysis/Afirma GSC OR ThyroSeq GC/ThyroSeq v3 MORE FREQUENTLY than once per member per episode of care.

Review the Medical Policy Statement section for medical necessity guidelines related to the use of EITHER Afirma Thyroid FNA Analysis/Afirma GSC OR ThyroSeq GC/ThyroSeq v3 to classify indeterminate nodules as benign or malignant (with only one of these tests Genetic/Genomic Testing and Pharmacogenetics

performed NO MORE THAN once per member per episode of care determined to be medically necessary).

d. When NOT specified as medically necessary according to applicable criteria in the Medical Policy Statement section of this policy, Plan Medical Director review is required for the use of microRNA profiling of fine-needle aspirates or thyroid tissue, gene expression testing of fine-needle aspirates or thyroid tissue, and/or next-generation sequencing in thyroid FNA and tissue samples with a predictive algorithm/classifier to determine if indeterminate thyroid nodules are benign or malignant when the presence of cancer cannot be ruled out by cytology (or for any other indication). Examples of these tests include but are not limited to the following: RosettaGX Reveal (Rosetta Genomics Ltd.), ThyGeNEXT, formerly called ThyGenX, (Interpace Diagnostics), ThyraMIR (Interpace Diagnostics), Afirma Gene Expression Classifier (GEC) (Veracyte Inc.), ThyroSeq v0, ThyroSeq v1, and ThyroSeq v.2 (University of Pittsburg Medical Center, CBLPath, Inc.).

e. Afirma Xpression Atlas (XA):

11. Tissue of Origin Testing:

Tissue of origin test (TOO) used to identify the primary tissue of origin when there is clinical uncertainty of a tumor’s primary origin is considered experimental and investigational for all indications/conditions UNLESS Plan-adopted InterQual® criteria are met. Clinical alternatives to the TOO are standard clinical and pathologic evaluation and further diagnostic tests such as blood tests, endoscopies, and radiological imaging, as appropriate for the individual’s condition.

12. Whole Exome Sequencing:

When Plan-adopted InterQual® criteria are NOT available or are NOT met for the requested indication for testing, whole exome sequencing (WES) is considered experimental and investigational when used for cancer indications, the diagnosis of genetic disorders, prenatal diagnosis, preimplantation testing of an embryo, used in the general population, and/or for any condition due to insufficient data on the analytical validity, clinical validity, and clinical utility of WES as an alternative to targeted genetic testing. Plan Medical Director approval is required for all prior authorization requests for WES (regardless of the sequencing technology utilized, including Sanger sequencing and/or next-generation sequencing).

Genetic/Genomic Testing and Pharmacogenetics

There is limited evidence from large comparative studies of the clinical utility of WES as a preferred clinical alternative to other appropriate screening and diagnostic techniques (even with primary findings from WES). In addition, incidental (secondary) findings from WES may not have high clinical significance, there may be limitations related to the analysis of incidental findings (including reduced technological reliability of the analysis and/or less scientific evidence available to interpret both positive and negative results) and/or interventions may not exist to prevent or ameliorate disease identified with WES. According to The American College of Obstetricians and Gynecologists (Committee Opinion Number 682), the routine use of whole genome or whole exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published.

13. Whole Genome Sequencing:

When Plan-adopted InterQual® criteria are NOT available or are NOT met for the requested indication for testing, met, whole genome sequencing (WGS) is considered experimental and investigational when used for cancer indications, the diagnosis of genetic disorders, prenatal testing, used in the general population, and/or for any other indications due to insufficient data on the analytical validity, clinical validity, and clinical utility of WGS as an alternative to targeted genetic testing. Plan Medical Director approval is required for all prior authorization requests for WGS (regardless of the sequencing technology utilized, including Sanger sequencing and/or next-generation sequencing).

WGS have been proposed to be more efficient than traditional sequencing methods in discovering the genetic causes of diseases, but there remain issues of error rates due to technical challenges and difficulty interpreting potential causative variants from variants of unknown significance generated for each patient. According to The American College of Obstetricians and Gynecologists (Committee Opinion Number 682), the routine use of whole- genome or whole-exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published.

Definitions Afirma Thyroid FNA Analysis/Afirma Genetic Sequence Classifier (GSC): Test (by Veracyte, Inc.) used to aid in thyroid nodule diagnosis by analyzing genetic alterations through the use of gene expression profiling in order to reduce unnecessary surgeries in patients with indeterminate thyroid nodules (i.e., thyroid nodules that are not clearly benign or malignant on fine-needle aspiration/FNA analysis). The test includes thyroid-specialized cytopathology and gene expression testing of numerous genes to determine patterns associated with benign findings on surgical biopsy. Indeterminate thyroid nodules are analyzed by the RNA-based GSC assay, to classify the indeterminate thyroid nodule as benign or suspicious. GSC-suspicious nodules undergo reflex testing using the Afirma Malignancy Classifiers, which includes the gene expression–based Afirma Medullary Thyroid Carcinoma (MTC) Classifier and DNA-based BRAF V600E mutation assay on the same fine-needle aspiration (FNA) sample. Indeterminate thyroid nodule biopsies are diagnosed in approximately 25 percent to 30 Genetic/Genomic Testing and Pharmacogenetics

percent of FNA samples. Patients with an indeterminate thyroid biopsy result may undergo surgical intervention, with partial (lobectomy or hemithyroidectomy) or total thyroidectomy treatment. While this treatment is necessary in some patients, 70 percent to 80 percent of indeterminate cases will prove to be benign after evaluation of the surgical thyroid tissue specimen. Patients with a benign diagnosis after surgical evaluation will have undergone an unnecessary surgery, with the potential for complications, and may face the lifelong need for thyroid hormone supplementation. Tests beyond cytological classification of thyroid nodules are needed in order to better identify the risk of malignancy.

Chromosomal Microarray Analysis (CMA): Also known as cytogenomic microarray analysis or cytogenomic constitutional (genome-wide) microarray analysis, CMA is a high-resolution, whole- genome screening used as a diagnostic tool to identify genetic abnormalities not detected with conventional cytogenetic analysis (e.g., karyotyping and FISH); CMA provides more refined testing by detecting smaller deletions and duplications in genomic material, potentially increasing the diagnostic yield in targeted populations. CMA collectively describes two (2) different laboratory techniques, comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays.

Copy Number Variants (CNVs): An alteration of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA.

Cytogenomic Neoplastia Microarray Analysis: Also known as neoplasia cytogenomic microarray analysis or neoplasia chromosomal microarray analysis (CMA), CMA testing is used to establish a diagnosis and/or prognosis for a patient with a malignancy by analyzing the tumor specimen to detect chromosome deletions, chromosome duplications and amplifications, and copy neutral loss of heterozygosity (LOH) across the entire genome. When CMA is requested to establish a diagnosis and/or prognosis for a member with a malignancy, InterQual® criteria must be met for the requested indication and prior authorization is required. If no InterQual® criteria are available for the specified indication for CMA testing, applicable medical necessity criteria and coding guidelines must be met in the Medical Policy Statement, Limitations, and Applicable Coding sections of this policy (rather than the Plan’s Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573), and Plan Medical Director review is required for individual consideration.

First-Degree Relative: A blood relative of an individual who shares approximately 50% of the individual’s genes as defined as a parent, full sibling, and children.

Gene Expression Profiling: A genetic test that measures the expression of a group of genes and translates the gene expression information into a risk score for a given disease or condition. Gene expression tests measure the activity of specific RNA in a tissue or bodily fluid at a given point in time to provide information on the individual’s current disease state, predict an individual’s response to treatment, and/or predict the likelihood of future disease with risk stratification. RNA levels change over time based on pathological conditions and environmental signals. This Plan policy (policy number OCA 3.7272) includes guidelines for gene expression testing used to predict response to drug Genetic/Genomic Testing and Pharmacogenetics

treatment (pharmacogenetics), gene expression testing to diagnose indeterminate nodules or tumors as benign or malignant; genomic testing of precancerous tumors to assess the risk of future cancer development; testing of protein biomarkers using diagnostic blood tests, urine tests, or other testing methods such as immunofluorescence and automated quantitative images of biopsy tissue (rather than gene expression of tumor tissue) to predict cancer recurrence with risk stratification based on an established algorithm; and/or genetic testing to classify a tumor into a main cancer type and subtype to identify the primary tissue of origin in a member when there is clinical uncertainty of a tumor’s primary origin.

Genetic Testing: According to U.S. Library of Medicine, genetic testing is defined as a type of medical test that identifies changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. More than 1,000 genetic tests are currently in use, and more are being developed. Several methods can be used for genetic testing:

1. Molecular genetic tests (or gene tests) study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder.

2. Chromosomal genetic tests analyze whole chromosomes to see if there are large genetic changes, such as an extra copy of a chromosome or missing DNA, that cause a genetic condition.

3. Biochemical genetic tests study the amount or activity level of proteins; abnormalities in either can indicate changes to the DNA that result in a genetic disorder. Many biochemical genetic diseases are known as “inborn errors of metabolism” because they are present at birth and disrupt a key metabolic pathway. Depending on the disease, tests can be developed to directly measure protein activity (direct measurement of enzyme activity), level of metabolites (indirect measurement of enzyme activity), and the size or quantity of protein (protein structure). These tests require a tissue sample in which the protein is present, typically blood, urine, amniotic fluid, or cerebrospinal fluid. Because gene products may be more unstable than DNA or RNA and can degrade quickly, the sample must be collected, stored properly, and shipped promptly according to the laboratory’s specifications. (Source: Genetic Alliance, 2009.)

Genome: The entire set of genetic instructions found in a cell. In humans, the genome consists of 23 pairs of chromosomes, found in the nucleus, as well as a small chromosome found in the cells' mitochondria. These chromosomes, taken together, contain approximately 3.1 billion bases of DNA sequence.

High-Risk: Includes members with a personal or family history of an autosomal dominant, autosomal recessive, X-linked recessive, or X-linked dominant condition; or individuals with a family history of a chromosomal abnormality, including chromosomal translocation or inversion.

Genetic/Genomic Testing and Pharmacogenetics

Immunohistochemistry (IHC): A laboratory test that uses antibodies to test for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the antigens in the tissue to light up under a microscope. Immunohistochemistry is used to help diagnose diseases, such as cancer. It may also be used to help tell the difference between different types of cancer.

Immunostaining: Any of several staining techniques that are used to detect specific proteins in a sample.

Microdeletions: Small segments of DNA missing from a specific chromosome.

Microsatellite Instability (MSI): A change that occurs in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different than the number of repeats that was in the DNA when it was inherited. The cause of microsatellite instability may be a defect in the ability to repair mistakes made when DNA is copied in the cell.

MicroRNA Profiling by Reverse Transcription Polymerase Chain Reaction (RT-PCR): RT-PCR is a variant of polymerase chain reaction (PCR) used in molecular biology to detect RNA expression. RT- PCR is a two-step process used to qualitatively detect gene expression by converting RNA into their complementary DNA (cDNA) sequences by reverse transcriptases (RT) transcripts. Quantitative RT-PCR (qRT-PCR) is a profiling test used to quantitatively measure the amplification of DNA with microRNA expression levels in RNA extracted from stained thyroid fine-needle aspiration (FNA) biopsy smears or cell blocks using fluorescent dyes. A proprietary algorithm classifier is used to differentiate thyroid nodules as benign or suspicious for malignancy. Examples of qRT-PCR tests include but are not limited to the RosettaGX Reveal by Rosetta Genomics Ltd.

Multigene Panel Tests: Tests that evaluate more than one (1) gene simultaneously to detect changes in these genes’ sequence and expression most commonly associated with certain diseases and other genes that may have limited evidence of an association to the disorder. Multigene panel tests may involve traditional exon-by-exon sequencing of targeted genes to identify genetic variants or use next- generation sequencing. Each laboratory establishes its own set of criteria for selecting the genes represented in a panel, even when panels are used for the same or similar clinical indications. The lack of regulatory oversight of genetic testing means that laboratories can change the components of a panel at any time, making it difficult to evaluate the clinical utility of multigene panel tests. Examples include but are not limited to the following: CancerNext Next-Gen Cancer Panel (Ambry Genetics Corp.), Comprehensive Personalized Medicine Panel (Alpha-Genomix Laboratories), Cytochrome P450 3A4 (CYP3A4) genotype testing (Mayo Medical Laboratories), Genecept Assay (Genomind), genTrue (True Health Diagnostics), MI TumorSeek (Caris Life Sciences), Endometrial Cancer Panel (GeneDx), GYNPlus (Ambry Genetics Corp.), High/Moderate Risk Panel (GeneDx Inc.), iGene Cancer Panel (ApolloGen Molecular Diagnostics Laboratory), PancNext Next-Gen Cancer Panel (Ambry Genetics Corp.), Pancreatic Cancer Panel, Preventest, SYMGENE68 NGS Cancer Panel (CellNetix Pathology & Laboratories LLC), and/or VistaSeq Hereditary Cancer Panel (Laboratory Corporation of America).

Genetic/Genomic Testing and Pharmacogenetics

Neonatal Alloimmune Thrombocytopenia (NAIT): NAT is caused by maternal antibodies raised against alloantigens carried on fetal platelets. Most cases of NAT are mild, but NAIT is a significant cause of morbidity and mortality in newborns. NAIT is the leading cause of severe thrombocytopenia in the fetus and neonate, can produce serious bleeding, intracranial hemorrhage and death, and is the leading cause of intracranial hemorrhage in full term infants.

Next Generation Sequencing (NGS, Next-Gen Sequencing, or Massively Parallel Sequencing): Genetic testing technique that can be used to sequence whole genomes, whole exomes, or constrained to targeted panels evaluating individual genes. NGS technology involves sequencing of millions of DNA fragments using the following three (3) levels of molecular analysis: (1) disease-targeted gene panels to sequence genes with an established role in the targeted disease, (2) exome sequencing of coding regions of the genome to include less common variants associated with the disease (i.e., a coding region is the segment of a gene that contains a protein-coding sequence called an exon in all 22,000 genes of the human genome); and/or (3) genome sequencing of both the coding and non-coding regions of the genome (i.e., the non-coding regions in between exons are called introns). Multiple sequencing platforms and different processes result in variability in test results among laboratories. Multigene panel tests may involve traditional exon-by-exon sequencing of targeted genes to identify genetic variants or use next-generation sequencing.

RNA Sequencing (RNA-Seq): Genetic testing that uses next-generation sequencing (NGS) to determine the sequence of the transcriptome, or complete set of RNA transcripts in a sample.

Second-Degree Relative: A blood relative of an individual who shares approximately 25% of the individual’s genes as defined as a grandparent, grandchildren, aunt, uncle, nephew, niece, and half- siblings.

Single Nucleotide Polymorphisms (SNPs): The most common type of genetic variation among individuals. Each SNP represents a difference in a single DNA building block, called a nucleotide. SNPs occur normally throughout a person’s DNA; normally these variations are found in the DNA between genes. If more than one (1) percent of a population does not carry the same nucleotide at a specific position in the DNA sequence, then this variation can be classified as a SNP. Most SNPs have no effect on health or development. When there is sufficient scientific evidence to support the clinical utility of testing, SNPs may help predict an individual’s response to certain drugs, susceptibility to environmental factors, risk of developing particular diseases, and/or susceptibility to genetic diseases within families.

Third-Degree Relative: A blood relative of an individual who shares 12.5% of the individual’s genes as defined as a biological first cousin, great grandmother, or great grandfather.

ThyGenX: Oncogene panel (by Interpace Diagnostics) of biomarkers commonly found in papillary and follicular thyroid cancers using next generation sequencing to evaluate point mutation associated with thyroid cancer.

Genetic/Genomic Testing and Pharmacogenetics

ThyraMIR: A microRNA (miRNA) gene expression classifier (by Interpace Diagnostics) that evaluates the expression of 10 miRNAs in patients with indeterminate thyroid FNA results when ThyGenX results are negative. ThyraMIR can identify malignancy in nodules that are negative for ThyGenX which potentially improves overall sensitivity and ability to detect malignancy.

ThyroSeq Next Generation Sequencing (NGS) Panel: Genetic test (by University of Pittsburgh Medical Center, CBL Path, Inc.) that includes sequencing of more than 60 genes and per manufacturer’s website is indicated when FNA cytology indicates atypical of uncertain significance (AUS) or follicular lesion of undetermined significance (FLUS), follicular neoplasm (FN) or suspicious for follicular neoplasm, or suspicious for malignancy. As of the third version of this assay, the test now includes gene expression with the ThyroSeq Genomic Classifier (GC)/ThyroSeq v3.

X-Linked Disorder: A chromosomal abnormality caused by mutations in genes on the X chromosome, one (1) of the two (2) sex chromosomes in each cell. In phenotypical females/individuals with two (2) X chromosomes, a mutation in one (1) of the two (2) copies of the gene in each cell is sufficient to cause an X-linked dominant disorder, and a mutation would have to occur in both copies of the gene to cause an X-linked recessive disorder. Because it is unlikely that phenotypical females (including individuals with typical female karyotype with two [2] X chromosomes) will have two (2) altered copies of this gene, phenotypical males (including individuals with typical male karyotype with only one [1] X chromosome) are affected by X-linked recessive disorders much more frequently than phenotypical females (including individuals with typical female karyotype with two [2] X chromosomes). The high clinical variability in female patients often makes the determination of an X-linked dominant disorder vs. an X-linked recessive disorder difficult. In phenotypical males (including individuals with typical male karyotype with only one [1] X chromosome), a mutation in the only copy of the gene in each cell causes an X-linked disorder. A characteristic of X-linked inheritance is that biological fathers (including biological parents with only one [1] X chromosome) cannot pass X-linked traits to their biological sons (including biological children with only one [1] X chromosome); this results in no phenotypical male-to- phenotypical male transmission. Examples of X-linked disorders include adrenoleukodystrophy, Alport syndrome, choroideremia, Fabry disease, fragile X syndrome, hemophilia A, hemophilia B, Hunter syndrome, incontinentia pigmenti, Lesch-Nyhan syndrome, muscular dystrophy, and X-linked intellectual disability. (Source: Genetic Home Reference from the U. S. Department of Health & Human Services.)

Whole Exome Sequencing (WES)/Whole Genome Sequencing (WGS): WES captures and sequences at a deep level the protein coding regions (called exons) of an individual’s genes using first-generation sequencing techniques or next-generation sequencing to detect disease-causing variants and discover gene targets. While exons represent only 1% of the genome, they account for approximately 85% of disease-causing variants. Through identification of variants across the exome, WES avoids the need to run multiple single-gene tests, which require prior information about variants affecting the disease. WES has been performed in a number of cancers, whereby comparison between tumor DNA and normal DNA from the same individual allows identification of variants specific to the tumor, which may provide information used for diagnosis and treatment. WES is targeted sequencing of the subset of the human genome that contains functionally important sequences of protein-coding DNA, while whole Genetic/Genomic Testing and Pharmacogenetics

genome sequencing (WGS) uses next-generation sequencing techniques to sequence both coding and non-coding regions of the genome. Because WES only evaluates the protein-coding regions of the human genome (exomes), WES is a more cost-effective alternative to WGS. WES produces a smaller, more manageable data set with faster turnaround time for analyses than WGS. WGS has the ability to detect structural variations located outside of the exome that may be related to many diseases and cannot be identified with WES. WGS is the most straightforward application of NGS, using DNA sequencing of individual DNA strands with WGS. WES and WGS have been proposed to be more efficient than traditional sequencing methods in discovering the genetic causes of diseases, but there remain issues of error rates due to technical challenges and difficulty interpreting potential causative variants from variants of unknown significance generated for each patient. Examples of tests include but are not limited to the following: Endometrial Cancer Panel (GeneDx), ExomeNext and ExomeNext- Rapid (Ambry Genetics), XomeDx™ test (GeneDx), mtSEEK Whole Mitochondrial Genome Analysis (Courtagen Life Sciences Inc.), and/or nucSEEK Comprehensive Sequence Analysis of Nuclear Mitochondrial Exome (Courtagen Life Sciences, Inc.). According to The American College of Obstetricians and Gynecologists (Committee Opinion Number 682), the routine use of whole genome or whole exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published.

Applicable Coding The Plan uses and adopts up-to-date Current Procedural Terminology (CPT) codes from the American Medical Association (AMA), International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) diagnosis codes developed by the World Health Organization and adapted in the United Stated by the National Center for Health Statistics (NCHS) of the Centers for Disease Control under the U.S. Department of Health and Human Services, and the Health Care Common Procedure Coding System (HCPCS) established and maintained by the Centers for Medicare & Medicaid Services (CMS). Since the AMA, NCHS, and CMS may update codes more frequently or at different intervals than InterQual® and Plan policy updates, the list of applicable codes included in InterQual® criteria and this Plan policy is for informational purposes only, may not be all inclusive, and is subject to change without prior notification. Whether a code is listed in the Applicable Coding section of this Plan policy or included in InterQual® criteria does not constitute or imply member coverage or provider reimbursement. Providers are responsible for reporting all services using the most up-to-date industry-standard procedure and diagnosis codes as published by the AMA, NCHS, and CMS at the time of the service.

Providers are responsible for obtaining prior authorization for the services specified in this Plan policy for ALL molecular and chromosomal genetic testing, even if an applicable code appropriately describing the service that is the subject of this Plan policy is not included in the Applicable Coding section of this Plan policy or not specified in InterQual® criteria (except for prenatal genetic screening tests for a member with one of the pregnancy diagnosis codes specified in the coding tables listed below). Biochemical genetic tests used to study the amount or activity level of proteins to indicate changes to the DNA require prior authorization when specified in the Plan’s Code Look-Up Tools, Prior Authorization Matrix, or a Plan medical policy available at www.bmchp.org for services provided to Genetic/Genomic Testing and Pharmacogenetics

BMC HealthNet Plan members (including Senior Care Options members) and at www.wellsense.org for testing requested for Well Sense Health Plan members. Coverage for services is subject to benefit eligibility under the member’s benefit plan. Refer to the member’s benefits document in effect at the time of the service to determine coverage or non-coverage as it applies to an individual member. Review the Plan’s reimbursement policies for Plan billing guidelines.

It is expected that genetic testing is clinically appropriate for the specified indication and that applicable Plan criteria or InterQual® criteria are met for all genetic testing, even when the prior authorization requirement is waived. (For example, a pregnancy diagnosis is not an indication for gene expression profiling of tumor tissue.) The medical necessity for genetic screening test(s) for the pregnant member (for both population-based screening and targeted population-based screening) must be documented in the member’s medical record; the Plan may validate with medical record audit the medical necessity of genetic testing when the prior authorization requirement is waived.

Prior authorization may or may not be required for medically necessary, non-invasive prenatal genetic screening, as specified below in the following sections when Plan criteria are met: Category 1 (Plan- specified, routine pregnancy and high-risk pregnancy ICD-10 primary diagnosis codes with corresponding procedure codes that do NOT require prior authorization when billed according to Plan guidelines), Category 2 (Plan-specified, high-risk pregnancy ICD-10 primary diagnosis codes with corresponding procedure codes that do NOT require prior authorization when billed according to Plan guidelines), Category 3 (procedure codes that require Plan authorization), and Category 4 (procedure codes considered experimental and investigational for all diagnosis codes). Review BOTH Category 1 and Category 2 for the complete list of procedure codes eligible for the prior authorization waiver when billed with a Plan-specified, high-risk pregnancy ICD-10 primary diagnosis code for a member. See the following medical policies for additional prenatal genetic tests which do not require prior authorization according to Plan guidelines: Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573, and Genetic Testing for Fragile X-Associated Disorders medical policy, policy number OCA 3.571. See the Medical Policy Statement section of this policy for genetic testing for members considering pregnancy. Prior authorization is REQUIRED for ALL molecular and chromosomal genetic testing (when testing is NOT provided to a pregnant member).

Genetic/Genomic Testing and Pharmacogenetics

Category 1: Plan-Specified, Routine Pregnancy and High-Risk Pregnancy ICD-10 Primary Diagnosis Codes with Corresponding Procedure Codes with Waived Prior Authorization

Plan-Specified, Description: Prior authorization is NOT required for medically necessary, non- Routine invasive prenatal genetic screening or other pregnancy-related indications for Pregnancy or a member when billed with one (1) of the following Plan-specified, routine High-Risk pregnancy or high-risk pregnancy ICD-10 primary diagnosis codes in Pregnancy ICD-10 combination with one (1) or more of the CPT and/or HCPCS codes listed in Primary Diagnosis Category 1, applicable medical necessity criteria are met (as specified in Codes InterQual® or in the Medical Policy Statement and Limitations sections of this policy), and the genetic test is ordered, administered, and processed by a participating provider and participating laboratory.

Plan notes: 1. Review BOTH Category 1 and Category 2 for the complete list of procedure codes for genetic testing eligible for the prior authorization waiver when billed with a Plan-specific high-risk pregnancy diagnosis code for a member. 2. A mother may include a female member, a member born with female reproductive organs, and/or a member with typical female karyotype with two (2) X chromosomes. 3. The pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options (SCO) members. O09.00-O09.93 Supervision of high-risk pregnancy O28.3 Abnormal ultrasonic finding on antenatal screening of mother O28.5 Abnormal chromosomal and genetic finding on antenatal screening of mother O35.0xx0 - Maternal care for known or suspected fetal abnormality and damage O35.9xx9 036.90 - 036.93 Maternal care for fetal problem, unspecified Z34.00 - Z34.93 Encounter for supervision of normal pregnancy Z36.0-Z36.9 Encounter for antenatal screening

CPT Codes Description: Codes covered when medically necessary.

Prior authorization is required UNLESS the following CPT codes are billed with one (1) of the Plan-specified, routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis codes listed in Category 1 (above), applicable medical necessity criteria are met (as specified in InterQual® or in the Medical Policy Statement and Limitations sections of this policy), and the genetic test is ordered, administered, and processed by a participating provider and participating laboratory. Cystic Fibrosis: The following prenatal tests are medically necessary as screening tools for when billed with a Plan-specified, routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis code. Genetic/Genomic Testing and Pharmacogenetics

81220 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; common variants (e.g., ACMG/ACOG guidelines)

Plan note: Code may be used for cystic fibrosis screening for a member considering pregnancy when the Plan’s applicable medical necessity criteria are met, as specified in the Medical Policy Statement section. 81221 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; known familial variants 81222 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; duplication/deletion variants 81223 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; full gene sequence

Plan note: According to the American College of Obstetricians and Gynecologists and the American College of Medical Genetics Update on Carrier Screening for Cystic Fibrosis Committee Opinion (number 486, reaffirmed 2014), “complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening because it may yield results that can be difficult to interpret. This type of testing is generally reserved for patients with cystic fibrosis [CF), patients with a family history of CF, males with congenital bilateral absence of the vas deferens, or newborns with a positive newborn screening result when mutation testing, using the standard 23-mutation panel, has a negative result. Because carrier screening detects most mutations, sequence analysis should only be considered after discussion with a genetics professional to determine if it will be of value to the evaluation after standard screening has been performed.” Testing may also be conducted on individuals born with male reproductive organs/typical male karyotype with only one (1) X chromosome with congenital bilateral absence of vas deferens. 81224 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; intron 8 poly-T analysis (e.g., male infertility)

Plan note: Male infertility includes conditions related to infertility in individuals born with male reproductive organs and/or individuals with typical male karyotype with only one (1) X chromosome. 81412 Ashkenazi Jewish associated disorders (e.g., Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Franconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1

Genetic/Genomic Testing and Pharmacogenetics

88235 Tissue culture for non-neoplastic disorders; amniotic fluid or chorionic villus cells

Plan note: Code may be used for chromosomal microarray analysis for prenatal genetic screening or other pregnancy-related indications. 88267 Chromosome analysis, amniotic fluid or chorionic villus, count 15 cells, 1 karyotype, with banding

Plan note: Code may be used for chromosomal microarray analysis for prenatal genetic screening or other pregnancy-related indications. 88269 Chromosome analysis, in situ for amniotic fluid cells, count cells from 6-12 colonies, 1 karyotype, with banding

Plan note: Code may be used for chromosomal microarray analysis for prenatal genetic screening or other pregnancy-related indications.

CPT Codes Description: Codes covered when medically necessary.

Prior authorization is required UNLESS the following CPT codes are billed with one (1) of the Plan-specified, routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis codes listed in Category 1 (above), applicable medical necessity criteria are met (as specified in InterQual® or in the Medical Policy Statement and Limitations sections of this policy), and the genetic test is ordered, administered, and processed by a participating provider and a participating laboratory. Trisomy 21 (Down Syndrome), Trisomy 18 (Edwards Syndrome) or Trisomy 13 (Patau Syndrome): The following prenatal tests of fetal aneuploidy are medically necessary as screening tools when billed with a Plan-specified, routine or high-risk pregnancy ICD-10 primary diagnosis code. 81420 Fetal chromosomal aneuploidy (e.g., trisomy 21, monosomy X) genomic sequence analysis panel, circulating cell-free fetal DNA in maternal blood, must include analysis of chromosomes 13, 18, and 21

Plan note: Code used for cell-free DNA (cfDNA) screening for testing of aneuploidies involving chromosomes 21 (T21 or Down syndrome), 18 (T18 or Edwards syndrome), and 13 (T13 or Patau syndrome). 81507 Fetal aneuploidy (trisomy 21, 18, and 13) DNA sequence analysis of selected regions using maternal plasma, algorithm reported as a risk score of each trisomy

Plan note: Code used for cell-free DNA (cfDNA) screening for testing of aneuploidies involving chromosomes 21 (T21 or Down syndrome), 18 (T18 or Edwards syndrome), and 13 (T13 or Patau syndrome).

Genetic/Genomic Testing and Pharmacogenetics

81508 Fetal congenital abnormalities, biochemical assays of two proteins [PAPP-A, hCG (any form)], utilizing maternal serum, algorithm reported as a risk score 88235 Tissue culture for non-neoplastic disorders; amniotic fluid or chorionic villus cells

Plan note: Code may be used for chromosomal microarray analysis for prenatal genetic screening or other pregnancy-related indications. 88261 Chromosome analysis; count 5 cells, 1 karyotype, with banding 88262 Chromosome analysis; count 15-20 Cells, 2 karyotypes, with banding 88263 Chromosome analysis; count 45 cells for mosaicism, 2 karyotypes, with banding 88264 Chromosome analysis; analyze 20-25 cells 88267 Chromosome analysis, amniotic fluid or chorionic villus, count 15 cells, 1 karyotype, with banding

Plan note: Code may be used for chromosomal microarray analysis for prenatal genetic screening or other pregnancy-related indications. 88271 Molecular cytogenetics; DNA probe, each (e.g., FISH) 88272 Molecular cytogenetics; chromosomal in situ hybridization, analyze 3-5 cells (e.g., for derivatives and markers) 88273 Molecular cytogenetics; chromosomal in situ hybridization, analyze 10-30 cells (e.g., for microdeletions) 88274 Molecular cytogenetics; interphase in situ hybridization, analyze 25-99 cells 88275 Molecular cytogenetics; interphase in situ hybridization, analyze 100-300 cells 88280 Chromosome analysis; additional karyotypes, each study 88291 Cytogenetics and molecular cytogenetics, interpretation and report

CPT Codes Description: Codes covered when medically necessary.

Prior authorization is required UNLESS the following CPT codes are billed with one (1) of the Plan-specified, routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis codes listed above in Category 1 (above), applicable medical necessity criteria are met (as specified in InterQual® or in the Medical Policy Statement and Limitations sections of this policy), and the genetic test is ordered, administered, and processed by a participating provider and a participating laboratory. Tay–Sachs: The following prenatal tests are medically necessary as a screening tool when billed with a Plan-specified, routine or high-risk pregnancy ICD-10 primary diagnosis code. 81255 HEXA (hexosaminidase A [alpha polypeptide]) (e.g., Tay-Sachs disease) gene Genetic/Genomic Testing and Pharmacogenetics

analysis, common variants (e.g., 1278insTATC, 1421+1G>C, G269S) 81403 Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2- 5 exons)

Plan note: This CPT code includes numerous types of tests. See CPT® codebook for detailed description of this code. 81406 Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons By DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)

Plan note: See CPT® codebook for detailed description of this code. This CPT code includes numerous types of tests, including MUTYH full gene sequence. 81412 Ashkenazi Jewish associated disorders (e.g., Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Franconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1 88235 Tissue culture for non-neoplastic disorders; amniotic fluid or chorionic villus cells

Plan note: Code may also be used when billing for prenatal genetic screening with chromosomal microarray analysis. 88291 Cytogenetics and molecular cytogenetics, interpretation and report

Plan note: Code may be used for chromosomal microarray analysis for prenatal genetic screening or other pregnancy-related indications.

Genetic/Genomic Testing and Pharmacogenetics

CPT Codes Description: Codes covered when medically necessary.

Prior authorization is required UNLESS the following CPT codes are billed with one (1) of the Plan-specified, routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis codes listed in Category 1 (above), applicable medical necessity criteria are met (as specified in InterQual® or in the Medical Policy Statement and Limitations sections of this policy), and the genetic test is ordered, administered, and processed by a participating provider and a participating laboratory. Additional Coding for Prenatal Tests: The following prenatal testing codes are medically necessary when billed for routine screening with a Plan-specified, routine pregnancy or high-risk pregnancy ICD- 10 primary diagnosis code. 81329 SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; dosage/deletion analysis (e.g., carrier testing), includes SMN2 (survival of motor neuron 2, centromeric) analysis, if performed

Plan note: Code may be used for spinal muscular atrophy (SMA) screening for a member considering pregnancy when the Plan’s applicable medical necessity criteria are met, as specified in the Medical Policy Statement section. 81336 SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; full gene sequence 81337 SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; known familial sequence variant(s) 81479 Unlisted molecular pathology procedure

Plan notes: 1. This code is waived for prior authorization for a Plan-specified routine primary pregnancy ICD-10 diagnosis code ONLY when related to screening for cystic fibrosis, trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome), and/or Tay–Sachs disease with testing specified above in Category 1 of this section or FMR1 related disorders (according to the guidelines included the Plan’s Genetic Testing for Fragile X-Associated Disorders medical policy, policy number OCA 3.571). 2. Billing with an unlisted code is subject to Plan audit and medical record review. 3. See the Limitations section for Plan guidelines for liquid biopsy testing. 81511 Fetal congenital abnormalities, biochemical assays of four analytes (AFP, uE3, hCG [any form], DIA) utilizing maternal serum, algorithm reported as a risk score (may include additional results from previous biochemical testing)

Genetic/Genomic Testing and Pharmacogenetics

88291 Cytogenetics and molecular cytogenetics, interpretation and report

Plan note: This code is waived for prior authorization for a Plan-specified routine primary pregnancy ICD-10 diagnosis code ONLY when related to screening for cystic fibrosis, trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome), and/or Tay–Sachs disease with testing specified above in Category 1 of this section. Code may be used for chromosomal microarray analysis for prenatal genetic screening or other pregnancy-related indications.

Category 2: Plan-Specified, High-Risk Pregnancy ICD-10 Primary Diagnosis Codes with Corresponding Procedure Codes with Waived Prior Authorization - In Addition to the Procedure Codes Specified in Category 1 (Applicable for BOTH Plan-Specified, Routine Pregnancy and High-Risk Pregnancy ICD-10 Primary Diagnosis Codes)

Plan-Specified, Description: Prior authorization is NOT required for medically necessary, non- High-Risk invasive prenatal genetic screening for a member ONLY when billed with one Pregnancy ICD-10 (1) of the following Plan-specified, high-risk pregnancy ICD-10 primary Primary Diagnosis diagnosis codes in combination with the CPT and/or HCPCS codes listed in Codes Category 1 or Category 2, applicable medical necessity criteria are met (as specified in InterQual® or in the Medical Policy Statement and Limitations sections of this policy), and the genetic test is ordered, administered, and processed by a participating provider and participating laboratory.

Plan notes: 1. Review BOTH Category 1 (applicable procedure codes for BOTH Plan- specified, routine pregnancy and high-risk pregnancy ICD-10 primary diagnosis codes) and Category 2 for the complete list of procedure codes for genetic testing eligible for the prior authorization waiver when billed with a Plan-specified, high-risk pregnancy ICD-10 primary diagnosis code for a member. 2. A mother may include a female member, a member born with female reproductive organs, and/or a member with typical female karyotype with two (2) X chromosomes. 3. The pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options (SCO) members. O09.511 - O09.519 Elderly primigravida O09.521-O09.529 Elderly multigravida O09.891 - O09.899 Supervision of other high-risk pregnancies O09.90-O09.93 Supervision of high-risk pregnancy, unspecified O28.3 Abnormal ultrasonic finding on antenatal screening of mother O28.5 Abnormal chromosomal and genetic finding on antenatal screening of mother Genetic/Genomic Testing and Pharmacogenetics

O35.0xx0 - Maternal care for known or suspected fetal abnormality and damage O35.9xx9 O36.4xx0 – Maternal care for intrauterine death O36.4xx9 O36.90 -O36.93 Maternal care for fetal problem, unspecified

CPT Codes Description: Codes covered when medically necessary.

Prior authorization is required UNLESS the following CPT codes are billed with one (1) of the Plan-specified, high-risk pregnancy ICD-10 primary diagnosis codes listed in Category 2 (above), applicable medical necessity criteria are met (as specified in Plan-adopted InterQual® or in the Medical Policy Statement and Limitations sections of this policy), and the genetic test is ordered, administered, and processed by a participating provider and a participating laboratory.

Plan notes: 1. Review BOTH Category 1 (applicable procedure codes for BOTH Plan- specified, routine pregnancy and high-risk pregnancy diagnosis codes) and Category 2 for the complete list of procedure codes for genetic testing eligible for the prior authorization waiver when billed with a Plan-specified, high-risk pregnancy ICD-10 primary diagnosis code for a member. 2. All Proprietary Laboratory Analysis (PLA) codes are ONLY payable for the Senior Care Options (SCO) product when the test is determined to be medically necessary for the SCO member. 81105 Human Platelet Antigen 1 genotyping (HPA-1), ITGB3 (integrin, beta 3 [platelet glycoprotein IIIa], antigen CD61 [GPIIIa]) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-1a/b (L33P) 81106 Human Platelet Antigen 2 genotyping (HPA-2), GP1BA (glycoprotein Ib [platelet], alpha polypeptide [GPIba]) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-2a/b (T145M) 81107 Human Platelet Antigen 3 genotyping (HPA-3), ITGA2B (integrin, alpha 2b [platelet glycoprotein IIb of IIb/IIIa complex], antigen CD41 [GPIIb]) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-3a/b (I843S) 81108 Human Platelet Antigen 4 genotyping (HPA-4), ITGB3 (integrin, beta 3 [platelet glycoprotein IIIa], antigen CD61 [GPIIIa]) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-4a/b (R143Q) 81109 Human Platelet Antigen 5 genotyping (HPA-5), ITGA2 (integrin, alpha 2 [CD49B,

Genetic/Genomic Testing and Pharmacogenetics

alpha 2 subunit of VLA-2 receptor] [GPIa]) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant (e.g., HPA-5a/b (K505E)) 81110 Human Platelet Antigen 6 genotyping (HPA-6w), ITGB3 (integrin, beta 3 [platelet glycoprotein IIIa, antigen CD61] [GPIIIa]) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-6a/b (R489Q) 81111 Human Platelet Antigen 9 genotyping (HPA-9w), ITGA2B (integrin, alpha 2b [platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41] [GPIIb]) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-9a/b (V837M) 81112 Human Platelet Antigen 15 genotyping (HPA-15), CD109 (CD109 molecule) (e.g., neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-15a/b (S682Y) 81120 IDH1 (isocitrate dehydrogenase 1 [NADP+], soluble) (e.g., glioma), common variants (e.g., R132H, R132C) 81121 IDH2 (isocitrate dehydrogenase 2 [NADP+], mitochondrial) (e.g., glioma), common variants (e.g., R140W, R172M) 81161 DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed 81168 CCND1/IGH (t(11;14)) (e.g., mantle cell lymphoma) translocation analysis, major breakpoint, qualitative and quantitative, if performed 81170 ABLI (ABL proto-oncogene 1, non-receptor tyrosine kinase) (e.g., acquired imatinib tyrosine kinase inhibitor resistance), gene analysis, variants in the kinase domain 81173 AR (androgen receptor) (e.g., spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; full gene sequence 81174 AR (androgen receptor) (e.g., spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; full gene sequence 81175 ASXL1 (additional sex combs like 1, transcriptional regulator) (e.g., myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; full gene sequence 81176 ASXL1 (additional sex combs like 1, transcriptional regulator) (e.g., myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; targeted sequence analysis (e.g., exon 12) 81177 ATN1 (atrophin 1) (e.g., dentatorubral-pallidoluysian atrophy) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81178 ATXN1 (ataxin 1) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81179 ATXN2 (ataxin 2) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles

Genetic/Genomic Testing and Pharmacogenetics

81180 ATXN3 (ataxin 3) (e.g., spinocerebellar ataxia, Machado-Joseph disease) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81181 ATXN7 (ataxin 7) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81182 ATXN8OS (ATXN8 opposite strand [non-protein coding]) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81183 ATXN10 (ataxin 10) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81184 CACNA1A (calcium voltage-gated channel subunit alpha1 A) (e.g., spinocerebellar ataxia) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles 81185 CACNA1A (calcium voltage-gated channel subunit alpha1 A) (e.g., spinocerebellar ataxia) gene analysis; full gene sequence 81186 CACNA1A (calcium voltage-gated channel subunit alpha1 A) (e.g., spinocerebellar ataxia) gene analysis; known familial variant 81187 CNBP (CCHC-type zinc finger nucleic acid binding protein) (e.g., myotonic dystrophy type 2) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81188 CSTB (cystatin B) (e.g., Unverricht-Lundborg disease) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles 81189 CSTB (cystatin B) (e.g., Unverricht-Lundborg disease) gene analysis; full gene sequence 81190 CSTB (cystatin B) (e.g., Unverricht-Lundborg disease) gene analysis; known familial variant(s) 81200 ASPA (aspartoacylase) (e.g., Canavan disease) gene analysis, common variants (e.g., E285A, Y231X) 81204 AR (androgen receptor) (e.g., spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; characterization of alleles (e.g., expanded size or methylation status) 81205 BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (e.g., Maple syrup urine disease) gene analysis, common variants (e.g., R183P, G278S, E422X) 81206 BCR/ABL1 (t[9;22]) (e.g., chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative 81207 BCR/ABL1 (t[9;22]) (e.g., chronic myelogenous leukemia) translocation analysis; minor breakpoint, qualitative or quantitative 81208 BCR/ABL1 (t[9;22]) (e.g., chronic myelogenous leukemia) translocation analysis; other breakpoint, qualitative or quantitative 81209 BLM (Bloom syndrome, RecQ helicase-like) (e.g., Bloom syndrome) gene analysis, 2281del6Ins7 variant 81218 CEBPA (CCAAT/enhancer binding protein[C/EBP], alpha) (e.g., acute myeloid leukemia), gene analysis, full gene sequence Genetic/Genomic Testing and Pharmacogenetics

81219 CALR (calreticulin) (e.g., myeloproliferative disorders), gene analysis, common variants in exon 9 81228 Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., Bacterial Artificial Chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis)

Genetic/Genomic Testing and Pharmacogenetics

81229 Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities

Plan notes: 1. The Plan’s Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573, includes guidelines for chromosomal microarray analysis (CMA) when used for the diagnosis of an adult or pediatric member with unexplained intellectual disability, developmental delay, symptoms or findings consistent with an autism spectrum disorder, and/or multiple congenital anomalies; applicable InterQual® criteria must be met for CMA for this indication and prior authorization is required. The Applicable Coding section of policy number OCA 3.573 includes the Plan’s list of high-risk pregnancy ICD-10 primary diagnosis codes and corresponding procedure codes waived for prior authorization for CMA when testing is used for prenatal genetic screening or other pregnancy-related indications such as fetal demise or stillbirth. 2. When CMA is requested to establish a diagnosis and/or prognosis for a member with a malignancy (testing also known as cytogenomic neoplastia microarray analysis) or for any other indication not specified above, InterQual® criteria must be met for the requested use and prior authorization is required. If no InterQual® criteria are available for the specified indication for CMA testing, applicable medical necessity criteria and coding guidelines must be met in the Medical Policy Statement, Limitations, and Applicable Coding sections of this Genetics/Genomic Testing and Pharmacogenetics medical policy and Plan Medical Director review is required for individual consideration. 81234 DMPK (DM1 protein kinase) (e.g., myotonic dystrophy type 1) gene analysis; evaluation to detect abnormal (expanded) alleles 81236 EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (e.g., myelodysplastic syndrome, myeloproliferative neoplasms) gene analysis, full gene sequence 81237 EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (e.g., diffuse large B-cell lymphoma) gene analysis, common variant(s) (e.g., codon 646) 81238 F9 (coagulation factor IX) (e.g., hemophilia B), full gene sequence 81239 DMPK (DM1 protein kinase) (e.g., myotonic dystrophy type 1) gene analysis; characterization of alleles (e.g., expanded size) 81240 F2 (prothrombin, coagulation factor II) (e.g., hereditary hypercoagulability) gene analysis, 20210G>A variant 81241 F5 (coagulation Factor V) (e.g., hereditary hypercoagulability) gene analysis, Leiden variant

Genetic/Genomic Testing and Pharmacogenetics

81242 FANCC (Fanconi anemia, complementation group C) (e.g., Fanconi anemia, type C) gene analysis, common variant (e.g., IVS4+4A>T) 81245 FLT3 (fms-related tyrosine kinase 3) (e.g., acute myeloid leukemia), gene analysis, internal tandem duplication (ITD) variants (i.e., exons 14, 15) 81246 FLT3 (fms-related tyrosine kinase 3) (e.g., acute myeloid leukemia), gene analysis; tyrosine kinase domain (TKD) variants (e.g., D835, I836) 81247 G6PD (glucose-6-phosphate dehydrogenase) (e.g., hemolytic anemia, jaundice), gene analysis; common variant(s) (e.g., A, A-) 81248 G6PD (glucose-6-phosphate dehydrogenase) (e.g., hemolytic anemia, jaundice), gene analysis; known familial variant(s) 81249 G6PD (glucose-6-phosphate dehydrogenase) (e.g., hemolytic anemia, jaundice), gene analysis; full gene sequence 81250 G6PC (glucose-6-phosphatase, catalytic subunit) (e.g., Glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (e.g., R83C, Q347X) 81251 GBA (glucosidase, beta, acid) (e.g., Gaucher disease) gene analysis, common variants (e.g., N370S, 84GG, L444P, IVS2+1G>A) 81252 GJB2 (gap junction protein, beta 2, 26kDa; connexin 26) (e.g., nonsyndromic hearing loss) gene analysis; full gene sequence 81253 GJB2 (gap junction protein, beta 2, 26kDa; connexin 26) (e.g., nonsyndromic hearing loss) gene analysis; known familial variants 81254 GJB6 (gas junction protein, beta 6, 30kDa, connexin 30) (e.g., nonsyndromic hearing loss) gene analysis, common variants (e.g., 309kb [del(GJB6-D13S1830)] and 232kb [del(GJB6-D13S1854)]) 81255 HEXA (hexosaminidase A [alpha polypeptide]) (e.g., Tay-Sachs disease) gene analysis, common variants (e.g., 1278insTATC, 1421+1G>C, G269S) 81256 HFE (hemochromatosis) (e.g., hereditary hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D) 81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, Constant Spring) 81258 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant 81259 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence 81260 IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) (e.g., familial dysautonomia) gene analysis, common variants (e.g., 2507+6T>C, R696P) 81261 IGH@ (Immunoglobulin heavy chain locus) (e.g., leukemias and lymphomas, B- cell), gene rearrangement analysis to detect abnormal clonal population(s); amplified methodology (e.g., polymerase chain reaction)

Genetic/Genomic Testing and Pharmacogenetics

81262 IGH@ (Immunoglobulin heavy chain locus) (e.g., leukemias and lymphomas, B- cell), gene rearrangement analysis to detect abnormal clonal population(s); direct probe methodology (e.g., Southern blot) 81263 IGH@ (Immunoglobulin heavy chain locus) (e.g., leukemia and lymphoma, B- cell), variable region somatic mutation analysis 81264 IGK@ (Immunoglobulin kappa light chain locus) (e.g., leukemia and lymphoma, B-cell), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) 81269 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants 81270 JAK2 (Janus kinase 2) (e.g., myeloproliferative disorder) gene analysis, P.Val617Phe (V617F) variant 81271 HTT (huntingtin) (e.g., Huntington disease) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles 81274 HTT (huntingtin) (e.g., Huntington disease) gene analysis; characterization of alleles (e.g., expanded size) 81278 IGH@/BCL2 (t(14;18)) (e.g., follicular lymphoma) translocation analysis, major breakpoint region (MBR) and minor cluster region (mcr) breakpoints, qualitative or quantitative 81279 JAK2 (Janus kinase 2) (e.g., myeloproliferative disorder) targeted sequence analysis (e.g., exons 12 and 13) 81283 IFNL3 (interferon, lambda 3) (e.g., drug response), gene analysis, rs12979860 variant 81284 HTT (huntingtin) (e.g., Huntington disease) gene analysis; characterization of alleles (e.g., expanded size) 81285 FXN (frataxin) (e.g., Friedreich ataxia) gene analysis; characterization of alleles (e.g., expanded size) 81286 FXN (frataxin) (e.g., Friedreich ataxia) gene analysis; full gene sequence 81287 MGMT (O-6-methylguanine-DNA methyltransferase) (e.g., glioblastoma multiforme ), promoter methylation analysis 81289 FXN (frataxin) (e.g., Friedreich ataxia) gene analysis; full gene sequence 81290 MCOLN1 (mucolipin 1) (e.g., Mucolipidosis, type IV) gene analysis, common variants (e.g., IVS3-2A>G, del6.4kb) 81291 MTHFR (5,10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C) 81302 MECP2 (methyl CpG binding protein 2) (e.g., Rett syndrome) gene analysis; full sequence analysis 81303 MECP2 (methyl CpG binding protein 2) (e.g., Rett syndrome) gene analysis; known familial variant 81304 MECP2 (methyl CpG binding protein 2) (e.g., Rett syndrome) gene analysis; duplication/deletion variants Genetic/Genomic Testing and Pharmacogenetics

81305 MYD88 (myeloid differentiation primary response 88) (e.g., Waldenstrom's macroglobulinemia, lymphoplasmacytic leukemia) gene analysis, p.Leu265Pro (L265P) variant 81306 NUDT15 (nudix hydrolase 15) (e.g., drug metabolism) gene analysis, common variant(s) (e.g., *2, *3, *4, *5, *6) 81310 NPM1 (nucleophosmin) (e.g., acute myeloid leukemia) gene analysis, exon 12 variants 81312 PABPN1 (poly[A] binding protein nuclear 1) (e.g., oculopharyngeal muscular dystrophy) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81314 PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) (e.g., gastrointestinal stromal tumor[GIST]), gene analysis, targeted sequence analysis (e.g., exons 12,18) 81315 PML/RARalpha, (t[15;17]), (promyelocytic leukemia/retinoic acid receptor alpha) (e.g., promyelocytic leukemia) translocation analysis; common breakpoints (e.g., intron 3 and intron 6), qualitative or quantitative 81316 PML/RARalpha, (t[15;17]), (promyelocytic leukemia/retinoic acid receptor alpha) (e.g., promyelocytic leukemia) translocation analysis; single breakpoint (e.g., intron 3, intron 6 or exon 6), qualitative or quantitative 81320 PLCG2 (phospholipase C gamma 2) (e.g., chronic lymphocytic leukemia) gene analysis, common variants (e.g., R665W, S707F, L845F) 81321 PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis 81322 PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; known familial variant 81323 PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; duplication/deletion variant 81324 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis 81325 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis 81326 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant 81328 SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (e.g., adverse drug reaction), gene analysis, common variant(s) (e.g., *5) 81330 SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (e.g., Niemann-Pick disease, Type A) gene analysis, common variants (e.g., R496L, L302P, FsP330) 81331 SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (e.g., Prader-Willi syndrome and/or Angelman syndrome), methylation analysis Genetic/Genomic Testing and Pharmacogenetics

81332 SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (e.g., alpha-1-antitrypsin deficiency), gene analysis, common variants (e.g., *S and *Z) 81333 TGFBI (transforming growth factor beta-induced) (e.g., corneal dystrophy) gene analysis, common variants (e.g., R124H, R124C, R124L, R555W, R555Q) 81334 RUNX1 (runt related transcription factor 1) (e.g., acute myeloid leukemia, familial platelet disorder with associated myeloid malignancy), gene analysis, targeted sequence analysis (e.g., exons 3-8) 81336 SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; full gene sequence 81337 SMN1 (survival of motor neuron 1, telomeric) (e.g., spinal muscular atrophy) gene analysis; known familial sequence variant(s) 81343 PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81344 TBP (TATA box binding protein) (e.g., spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (e.g., expanded) alleles 81345 TERT (telomerase reverse transcriptase) (e.g., thyroid carcinoma, glioblastoma multiforme) gene analysis, targeted sequence analysis (e.g., promoter region) 81357 U2AF1 (U2 small nuclear RNA auxiliary factor 1) (e.g., myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variants (e.g., S34F, S34Y, Q157R, Q157P) 81360 ZRSR2 (zinc finger CCCH-type, RNA binding motif and serine/arginine-rich 2) (e.g., myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variant(s) (e.g., E65fs, E122fs, R448fs) 81361 HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); common variant(s) (e.g., HbS, HbC, HbE) 81362 HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); known familial variant(s) 81363 HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); duplication/deletion variant(s) 81364 HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); full gene sequence 81400 Molecular pathology procedure, Level 1 (e.g., identification of single germline variant [e.g., SNP] by techniques such as restriction enzyme digestion or melt curve analysis)

Plan note: This CPT code includes numerous types of tests, including F5 HR2 variant analysis. See CPT® codebook for detailed description of this code.

Genetic/Genomic Testing and Pharmacogenetics

81401 Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using non-sequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)

Plan note: This CPT code includes numerous types of tests, including EML4/ALK translocation or inversion analysis. See CPT® codebook for detailed description of this code. 81402 Molecular pathology procedure, Level 3 (e.g., >10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD])

Plan note: This CPT code includes numerous types of tests. See CPT® codebook for detailed description of this code. 81403 Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2- 5 exons)

Plan note: This CPT code includes numerous types of tests. See CPT® codebook for detailed description of this code. 81404 Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

Plan note: This CPT code includes numerous types of tests, including CDKN2A, NLGN4X, and RAS sequence analyses. See CPT® codebook for detailed description of this code. 81405 Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons), regionally targeted cytogenomic array analysis

Plan note: This CPT code may be used to bill for numerous types of tests (e.g., chromosomal microarray analysis). See CPT® codebook for detailed description of this code.

Genetic/Genomic Testing and Pharmacogenetics

81406 Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons By DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)

Plan note: See CPT® codebook for detailed description of this code. This CPT code includes numerous types of tests, including MUTYH full gene sequence. 81407 Molecular pathology procedure, Level 8 (e.g., analysis Of 26-50 exons By DNA sequence analysis, mutation scanning or duplication/deletion variants Of >50 exons, sequence analysis of multiple genes on one platform)

Plan note: This CPT code includes numerous types of tests. See CPT® codebook for detailed description of this code. 81408 Molecular pathology procedure, Level 9 (e.g., analysis Of >50 exons in a single gene By DNA sequence analysis)

Plan note: This CPT code includes numerous types of tests. See CPT® codebook for detailed description of this code. 81410 Aortic dysfunction or dilation (e.g., Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, and MYLK 81411 Aortic dysfunction or dilation (e.g., Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1 81440 Nuclear encoded mitochondrial genes (e.g., neurologic or myopathic phenotypes), genomic sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10, DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, SUCLA2, SUCLG1, TAZ, TK2, and TYMP 81442 Noonan spectrum disorders (e.g., Noonan Syndrome, cardio-facio-cutaneous syndrome, Costello Syndrome, LEOPARD syndrome, Noonan-like syndrome), genomic sequence analysis panel, must include sequencing of at least 12 genes, including BRAF,CBL,HRAS,KRAS,MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2 and SOS1 81443 Genetic testing for severe inherited conditions (e.g., cystic fibrosis, Ashkenazi Jewish-associated disorders [e.g., Bloom syndrome, Canavan disease, Fanconi anemia type C, mucolipidosis type VI, Gaucher disease, Tay-Sachs disease], beta hemoglobinopathies, phenylketonuria, galactosemia), genomic sequence analysis panel, must include sequencing of at least 15 genes (e.g., ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH)

Genetic/Genomic Testing and Pharmacogenetics

81448 Hereditary peripheral neuropathies (e.g., Charcot-Marie-Tooth, spastic paraplegia), genomic sequence analysis panel, must include sequencing of at least 5 peripheral neuropathy-related genes (e.g., BSCL2, GJB1, MFN2, MPZ, REEP1, SPAST, SPG11, SPTLC1) 81460 Whole mitochondrial genome (e.g., Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection 81465 Whole mitochondrial genome large deletion analysis panel (e.g., Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed 81470 X-linked intellectual disability (XLID) (e.g., syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2 81471 X-linked intellectual disability (XLID) (e.g., syndromic and non-syndromic XLID); duplication/deletion gene analysis, must include analysis of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2 81479 Unlisted molecular pathology procedure

Plan notes: 1. Providers should use HCPCS code G0452 when billing the interpretation and report for this service. 2. Code may be used for BRACAnalysis CDx®. 3. See the applicable medical necessity criteria in the Medical Policy Statement and Limitations sections of this policy (rather than InterQual® criteria) for the use of ThyroSeq testing (University of Pittsburgh Medical Center, CBLPath, Inc.). 4. Review the applicable criteria in the Limitations section of this policy (rather than InterQual® criteria) for the use of genetic testing to confirm the identity of laboratory specimens; e.g., know error® DNA Specimen Provenance Assay (Strand Diagnostics, LLC) or ToxProtect DNA-verified Urine Drug Test (Genotox Laboratories).

Genetic/Genomic Testing and Pharmacogenetics

81599 Unlisted multianalyte assay with algorithmic analysis

Plan note: Code may be used for cell-free DNA (cfDNA) screening for additional testing options for cfDNA screening beyond testing of aneuploidies involving chromosomes 21, 18, and 13, such as the sex (X and Y) chromosomes for aneuploidies such as monosomy X (45, X or Turner syndrome), 47, XXY (Klinefelter syndrome), 47,XXX (trisomy X syndrome), and 47,XYY (Jacob’s syndrome). 88230 Tissue culture for non-neoplastic disorders; lymphoctye 88233 Tissue culture for non-neoplastic disorders; skin or other solid tissue biopsy 88240 Cryopreservation, freezing and storage of cells, each cell line 88241 Thawing and expansion of frozen cells, each aliquot 88245 Chromosome analysis for breakage syndromes; baseline Sister Chromatid Exchange (SCE), 20-25 cells 88248 Chromosome analysis for breakage syndromes; baseline breakage, score 50-100 cells, count 20 cells, 2 karyotypes (e.g., for ataxia telangiectasia, Fanconi anemia, fragile X) 88249 Chromosome analysis for breakage syndromes; score 100 cells, clastogen stress (e.g., diepoxybutane, mitomycin C, ionizing radiation, UV radiation) 88283 Chromosome analysis; additional specialized banding technique (e.g., NOR, C- banding) 88285 Chromosome analysis; additional cells counted, each study 88289 Chromosome analysis; additional high resolution study 88299 Unlisted cytogenetic study

HCPCS Codes Description: Codes covered when medically necessary. The HCPCS codes in this section are NOT payable for the Senior Care Options (SCO) product.

Prior authorization is required UNLESS the following HCPCS codes are billed with one (1) of the routine or high-risk primary pregnancy ICD-10 diagnosis codes listed above, applicable medical necessity criteria are met (as specified in InterQual® or in the Medical Policy Statement and Limitations sections of this policy when applicable InterQual® criteria are NOT adopted by the Plan or NOT available), and the genetic test is ordered, administered, and processed by a participating provider and a participating laboratory. S3841 Genetic testing for retinoblastoma S3842 Genetic testing for Von Hippel-Lindau disease S3844 DNA analysis of the connexin 26 gene (GJB2) for susceptibility to congenital, profound deafness S3845 Genetic testing for alpha-thalassemia S3846 Genetic testing for hemoglobin E beta-thalassemia

Genetic/Genomic Testing and Pharmacogenetics

S3849 Genetic testing for Niemann-Pick disease S3850 Genetic testing for sickle cell anemia S3853 Genetic testing for myotonic muscular dystrophy S3861 Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for suspected Brugada Syndrome S3865 Comprehensive gene sequence analysis for hypertrophic cardiomyopathy S3866 Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family S3870 Comparative genomic hybridization (CGD) microarray testing for developmental delay, autism spectrum disorder and/or intellectual disability

Category 3: Procedure Codes that Require Plan Authorization for All Diagnosis Codes

CPT Codes Description: Codes covered when medically necessary. All Industry- ALL industry-standard billing codes for genetic testing REQUIRES prior Standard Billing authorization for ANY diagnosis code (UNLESS the procedure code is listed above Codes for Genetic in Category 1 or Category 2 and criteria are met for the prior authorization waiver Testing NOT for pregnant members). Included in Category 1, Plan note: Genetic testing is considered medically necessary when Plan-adopted Category 2, or InterQual® criteria are met or criteria specified in the Medical Policy Statement Category 4 section of this policy are met for the requested indication for testing. Examples: Below are examples of procedure codes for genetic testing that requires prior authorization when billed with ANY diagnosis code and the prior authorization waiver for pregnant members does NOT apply. This is NOT an all-inclusive list. All Proprietary Laboratory Analysis (PLA) codes are ONLY payable for the Senior Care Options (SCO) product when the test is determined to be medically necessary for the SCO member. 0009U Oncology (breast cancer), ERBB2 (HER2) copy number by FISH, tumor cells from formalin fixed paraffin embedded tissue isolated using image-based dielectrophoresis (DEP) sorting, reported as ERBB2 gene amplified or non- amplified

Plan note: PLA code is only billed when the DEPArray HER2 test is performed. Code is ONLY payable for the SCO product. 0016U Oncology (hematolymphoid neoplasia), RNA, BCR/ABL1 major and minor breakpoint fusion transcripts, quantitative PCR amplification, blood or bone marrow, report of fusion not detected or detected with quantitation

Plan note: PLA code is only billed when the BCR-ALB 1 major and minor breakpoint fusion transcripts test is performed. Code is ONLY payable for the SCO product. 0017U Oncology (hematolymphoid neoplasia), JAK2 mutation, DNA, PCR amplification of Genetic/Genomic Testing and Pharmacogenetics

exons 12-14 and sequence analysis, blood or bone marrow, report of JAK2 mutation not detected or detected

Plan note: PLA code is only billed when the JAK2 Mutation (University of Iowa, Department of Pathology) test is performed. Code is ONLY payable for the SCO product. 0022U Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence/absence of variants and associated therapy(ies) to consider

Plan note: This PLA code is only billed when the Oncomine Dx Target Test (Thermo Fisher Scientific) is billed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member. 0023U Oncology (acute myelogenous leukemia), DNA, genotyping of internal tandem duplication, p.D835, p.I836, using mononuclear cells, reported as detection or non-detection of FLT3 mutation and indication for or against the use of midostaurin

Plan note: This PLA code is only billed when the LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member. 0026U Oncology (thyroid), DNA and mRNA of 112 genes, next-generation sequencing, fine needle aspirate of thyroid nodule, algorithmic analysis reported as a categorical result

Plan note: See the applicable medical necessity criteria in the Medical Policy Statement and Limitations sections of this policy (rather than InterQual® criteria) for the use of ThyroSeq tests (University of Pittsburgh Medical Center, CBLPath, Inc.). 0070U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, common and select rare variants (i.e., *2, *3, *4, *4N, *5, *6, *7, *8, *9, *10, *11, *12, *13, *14A, *14B, *15, *17, *29, *35, *36, *41, *57, *61, *63, *68, *83, *xN)

Plan note: This PLA test only billed when the CYP2D6 Common Variants and Copy Number (Mayo Clinic) test is performed. Code IS ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0071U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, full gene sequence (List separately in addition to code

Genetic/Genomic Testing and Pharmacogenetics

for primary procedure) (Use 0071U in conjunction with 0070U)

Plan note: This PLA code is only billed when the CYP2D6 Full Gene Sequencing (Mayo Clinic) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0072U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., CYP2D6-2D7 hybrid gene) (List separately in addition to code for primary procedure) (Use 0072U in conjunction with 0070U)

Plan note: This PLA code is only billed when the CYP2D6-2D7 Hybrid Gene Targeted Sequence Analysis (Mayo Clinic) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0073U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., CYP2D7-2D6 hybrid gene) (List separately in addition to code for primary procedure) (Use 0073U in conjunction with 0070U)

Plan note: This PLA code is only billed when the CYP2D7-2D6 Hybrid Gene Targeted Sequence Analysis (Mayo Clinic) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0074U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., non-duplicated gene when duplication/multiplication is trans) (List separately in addition to code for primary procedure) (Use 0074U in conjunction with 0070U)

Plan note: This PLA code is only billed when the CYP2D6 transduplication/ multiplication non-duplicative gene targeted sequence analysis (Mayo Clinic) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0075U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., 5’ gene duplication/multiplication) (List separately in addition to code for primary procedure) (Use 0075U in conjunction with 0070U)

Plan note: This PLA code is only billed when the CYP2D6 5’ gene duplication/ multiplication targeted sequence analysis (Mayo Clinic) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member. 0076U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., 3’ gene duplication/ multiplication) (List separately in addition to code for primary procedure) (Use 0076U in conjunction with 0070U)

Plan note: This PLA code is only billed when the CYP2D6 3’ gene duplication/ multiplication targeted sequence analysis (Mayo Clinic) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0140U Infectious disease (fungi), fungal pathogen identification, DNA (15 fungal targets), blood culture, amplified probe technique, each target reported as detected or not detected

Plan note: This PLA code is only billed when the ePlex® BCID Fungal Pathogens Panel (GenMark Diagnostics, Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0141U Infectious disease (bacteria and fungi), gram-positive organism identification and drug resistance element detection, DNA (20 gram-positive bacterial targets, 4 resistance genes, 1 pan gram-negative bacterial target, 1 pan Candida target), blood culture, amplified probe technique, each target reported as detected or not detected

Plan note: This PLA code is only billed when the ePlex® BCID Gram Positive Panel (GenMark Diagnostics, Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member.

Genetic/Genomic Testing and Pharmacogenetics

0142U Infectious disease (bacteria and fungi), gram-negative bacterial identification and drug resistance element detection, DNA (21 gram-negative bacterial targets, 6 resistance genes, 1 pan gram-positive bacterial target, 1 pan Candida target), amplified probe technique, each target reported as detected or not detected

Plan note: This PLA code is only billed when the ePlex® BCID Gram Negative Panel (GenMark Diagnostics, Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member. 0151U Infectious disease (bacterial or viral respiratory tract infection), pathogen specific nucleic acid (DNA or RNA), 33 targets, real-time semi-quantitative PCR, bronchoalveolar lavage, sputum, or endotracheal aspirate, detection of 33 organismal and antibiotic resistance genes with limited semi-quantitative results

Plan note: This PLA code is only billed when the BioFire® FilmArray® Pneumonia Panel (BioFire Diagnostics) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member. 0152U Infectious disease (bacteria, fungi, parasites, and DNA viruses), DNA, PCR and next-generation sequencing, plasma, detection of >1,000 potential microbial organisms for significant positive pathogens

Plan note: This PLA code is only billed when the Karius® Test (Karius Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member. 0208U Oncology (medullary thyroid carcinoma), mRNA, gene expression analysis of 108 genes, utilizing fine needle aspirate, algorithm reported as positive or negative for medullary thyroid carcinoma

Plan note: This PLA code is only billed when the Afirma Medullary Thyroid Carcinoma (MTC) Classifier (Veracyte, Inc.) is performed. Code is ONLY payable for the SCO product. Review the Medical Policy Statement section of this policy. 81191 NTRK1 (neurotrophic receptor tyrosine kinase 1) (e.g., solid tumors) translocation analysis 81192 NTRK2 (neurotrophic receptor tyrosine kinase 2) (e.g., solid tumors) translocation analysis 81193 NTRK3 (neurotrophic receptor tyrosine kinase 3) (e.g., solid tumors) translocation analysis 81194 NTRK (neurotrophic-tropomyosin receptor tyrosine kinase 1, 2, and 3) (e.g., solid tumors) translocation analysis 81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (e.g., colon cancer, melanoma), gene analysis, V600 variant(s) 81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (e.g., drug

Genetic/Genomic Testing and Pharmacogenetics

metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17) 81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN) 81227 CYP2C9 (Cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6) 81230 CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (e.g., drug metabolism), gene analysis, common variant(s) (e.g., *2, *22) 81231 CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *7) 81232 DPYD (dihydropyrimidine dehydrogenase) (e.g., 5-fluorouracil/5-FU and capecitabine drug metabolism), gene analysis, common variant(s) (e.g., *2A, *4, *5, *6) 81233 BTK (Bruton's tyrosine kinase) (e.g., chronic lymphocytic leukemia) gene analysis, common variants (e.g., C481S, C481R, C481F) 81235 EGFR (epidermal growth factor receptor) (e.g., non-small cell lung cancer) gene analysis, common variants (e.g., exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q) 81272 KIT (v-kit-Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (e.g., gastrointestinal stromal tumor [GIST], acute myeloid leukemia, melanoma), gene analysis, targeted sequence analysis (e.g., exons 8,11,13,17,18) 81273 KIT(v-kit-Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (e.g., mastocytosis), gene analysis, D816 variant(s) 81275 KRAS (Kirsten rat sarcoma viral oncogene homolog) (e.g., carcinoma) gene analysis, variants in exon 2 (e.g., codons 12 And 13) 81276 KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene) (e.g., carcinoma) gene analysis, variants in codons 12 And 13; additional variants(s) (e.g., codon 61, codon 146) 81277 Cytogenomic neoplasia (genome-wide) microarray analysis, interrogation of genomic regions for copy number and loss-of-heterozygosity variants for chromosomal abnormalities

Plan notes: 1. When chromosomal microarray analysis (CMA) is requested to establish a diagnosis and/or prognosis for a member with a malignancy (testing also known as cytogenomic neoplastia microarray analysis), InterQual® criteria must be met for the requested indication. If no InterQual® criteria are available for the specified indication for CMA testing, applicable medical necessity criteria and coding guidelines must be met in the Medical Policy Statement, Limitations, and Applicable Coding sections of this policy and Plan Medical Director review is required for individual consideration. 2. The Plan’s Chromosomal Microarray Analysis for Unexplained Intellectual Genetic/Genomic Testing and Pharmacogenetics

Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573, includes medical necessity guidelines for CMA when used for the diagnosis of an adult or pediatric member with unexplained intellectual disability, developmental delay, symptoms or findings consistent with an autism spectrum disorder, and/or multiple congenital anomalies; applicable InterQual® criteria must be met for CMA for this indication. Policy number OCA 3.573 lists the primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization for CMA for prenatal genetic screening and other pregnancy-related indications such fetal demise or stillbirth. 81311 NRAS (Neuroblastoma RAS viral[v-ras] oncogene homolog) (e.g., colorectal carcinoma), gene analysis, variants in exon 2 (e.g., codons 12 and 13) and exon 3 (e.g., codon 61) 81313 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (e.g., prostate cancer) 81335 TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3) 81338 MPL (MPL proto-oncogene, thrombopoietin receptor) (e.g., myeloproliferative disorder) gene analysis; common variants (e.g., W515A, W515K, W515L, W515R) 81339 MPL (MPL proto-oncogene, thrombopoietin receptor) (e.g., myeloproliferative disorder) gene analysis; sequence analysis, exon 10 81346 TYMS (thymidylate synthetase) (e.g., 5-fluorouracil/5-FU drug metabolism), gene analysis, common variant(s) (e.g., tandem repeat variant) 81347 SF3B1 (splicing factor [3b] subunit B1) (e.g., myelodysplastic syndrome/acute myeloid leukemia) gene analysis, common variants (e.g., A672T, E622D, L833F, R625C, R625L) 81340 TRB@ (T cell antigen receptor, beta) (e.g., leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using amplification methodology (e.g., polymerase chain reaction) 81341 TRB@ (T cell antigen receptor, beta) (e.g., leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using direct probe methodology (e.g., Southern blot) 81342 TRG@ (T cell antigen receptor, gamma) (e.g., leukemia and lymphoma), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) 81348 SRSF2 (serine and arginine-rich splicing factor 2) (e.g., myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variants (e.g., P95H, P95L)

Genetic/Genomic Testing and Pharmacogenetics

81350 UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (e.g., irinotecan metabolism), gene analysis, common variants (e.g., *28, *36, *37) 81351 TP53 (tumor protein 53) (e.g., Li-Fraumeni syndrome) gene analysis; full gene sequence 81352 TP53 (tumor protein 53) (e.g., Li-Fraumeni syndrome) gene analysis; targeted sequence analysis (e.g., 4 oncology) 81353 TP53 (tumor protein 53) (e.g., Li-Fraumeni syndrome) gene analysis; known familial variant 81355 VKORC1 (vitamin K epoxide reductase complex, subunit 1) (e.g., warfarin metabolism), gene analysis, common variants (e.g., -1639G>A, c.173+1000C>T) 81413 Cardiac ion channelopathies (e.g., Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); genomic sequence analysis panel, must include sequencing of at least 10 genes, including ANK2, CASQ2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, RYR2, and SCN5A 81414 Cardiac ion channelopathies (e.g., Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); duplication/deletion gene analysis panel, must include analysis of at least 2 genes, including KCNH2 and KCNQ1 81415 Exome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis

Genetic/Genomic Testing and Pharmacogenetics

81416 Exome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (e.g., parents, siblings) (List separately in addition to code for primary procedure)

Plan notes: 1. The Plan considers exome sequence analysis to be experimental and investigational when InterQual® criteria are NOT met, as specified in the Limitations section. Plan Medical Director review is required for all prior authorization requests. 2. According to The American College of Obstetricians and Gynecologists (Committee Opinion Number 682), the routine use of whole-exome sequencing for prenatal diagnosis is NOT recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published. 81419 Epilepsy genomic sequence analysis panel, must include analyses for ALDH7A1, CACNA1A, CDKL5, CHD2, GABRG2, GRIN2A, KCNQ2, MECP2, PCDH19, POLG, PRRT2, SCN1A, SCN1B, SCN2A, SCN8A, SLC2A1, SLC9A6, STXBP1, SYNGAP1, TCF4, TPP1, TSC1, TSC2, and ZEB2 81430 Hearing loss (e.g., nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS1 81431 Hearing loss (e.g., nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes

Genetic/Genomic Testing and Pharmacogenetics

81434 Hereditary retinal disorders (e.g., retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy), genomic sequence analysis panel, must include sequencing of at least 15 genes, including ABCA4, CNGA1, CRB1, EYS, PDE6A, PDE6B, PRPF31, PRPH2, RDH12, RHO, RP1, RP2, RPE65, RPGR, and USH2A 81437 Hereditary neuroendocrine tumor disorders (e.g., medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paragaglioma), genomic sequence analysis panel, must include sequencing of at least 6 genes, including MAX,SDHB,SDHC,SDHD,TMEM127 and VHL 81438 Hereditary neuroendocrine tumor disorders (e.g., medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paragaglioma), genomic sequence analysis panel, must include sequencing of at least 6 genes, including MAX,SDHB,SDHC,SDHD,TMEM127 and VHL; duplication/deletion analysis panel, must include analyses for SDHB, SDHC,SDHD and VHL 81439 Inherited cardiomyopathy (e.g., hypertrophic cardiomyopathy, dilated arrhythmogenic right ventricular cardiomyopathy), genomic sequence analysis panel, must include sequencing of at least 5 cardiomyopathy-related genes (e.g. DSG2, MYBPC3, MYH7, PKP2, and TTN) 81445 Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, 5-50 genes (e.g., ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed 81450 Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA analysis, and RNA analysis when performed, 5-50 genes (e.g., BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed 81455 Targeted genomic sequence analysis panel, solid organ neoplasm or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (e.g., ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, NRAS, MLL,NPM1, NRAS, MET,NOTCH1, PDGFRA, PDGFRB, PGR,PIK3CA, PTEN, RET), interrogation for sequence variants, and copy number variants or rearrangements, if performed 81490 Autoimmune (rheumatoid arthritis), analysis of 12 biomarkers using immunoassays, utilizing serum, prognostic algorithm reported as a disease activity score 81493 Coronary artery disease, mRNA, gene expression profiling by real-time RT-PCR of 23 genes, utilizing whole peripheral blood, algorithm reported as a risk score 81522 Oncology (breast), mRNA, gene expression profiling by RT-PCR of 12 genes (8 content and 4 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence risk score 81529 Oncology (cutaneous melanoma), mRNA, gene expression profiling by real-time

Genetic/Genomic Testing and Pharmacogenetics

RT-PCR of 31 genes (28 content and 3 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis 81535 Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; first single drug or drug combination 81536 Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; each additional single drug or drug combination (List separately in addition to code for primary procedure) 81538 Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival 81546 Oncology (thyroid), mRNA, gene expression analysis of 10,196 genes, utilizing fine needle aspirate, algorithm reported as a categorical result (e.g., benign or suspicious) 81551 Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy 81542 Oncology (prostate), mRNA, microarray gene expression profiling of 22 content genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as metastasis risk score 81552 Oncology (uveal melanoma), mRNA, gene expression profiling by real-time RT- PCR of 15 genes (12 content and 3 housekeeping), utilizing fine needle aspirate or formalin-fixed paraffin-embedded tissue, algorithm reported as risk of metastasis 81554 Pulmonary disease (idiopathic pulmonary fibrosis [IPF]), mRNA, gene expression analysis of 190 genes, utilizing transbronchial biopsies, diagnostic algorithm reported as categorical result (e.g., positive or negative for high probability of usual interstitial pneumonia [UIP]) 81595 Cardiology (heart transplant), mRNA, gene expression profiling by real-time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing sub fraction of peripheral blood, algorithm reported as a rejection risk score

Plan note: For Senior Care Options (SCO) members only, review the National Coverage Determination (NCD) for Heartsbreath Test for Heart Transplant Rejection (260.10) for coverage guidelines; criteria may be accessed at: https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=325&ncdver=1&DocID=260.10&SearchType=Advanced&bc=I AAAABAAAAAA& 87563 Infectious agent detection by nucleic acid (DNA or RNA); Mycoplasma genitalium, amplified probe technique 88237 Tissue culture for neoplastic disorders; bone marrow, blood cells

Genetic/Genomic Testing and Pharmacogenetics

88239 Tissue culture for neoplastic disorders; solid tumor

HCPCS Codes Description: Codes covered when medically necessary. All Industry- ALL industry-standard billing codes for genetic testing REQUIRES prior Standard Billing authorization for ANY diagnosis code (UNLESS the procedure code is listed above Codes for Genetic in Category 1 or Category 2 and criteria are met for the prior authorization waiver Testing NOT for pregnant members). Included in Category 1, Plan note: Genetic testing is considered medically necessary when Plan-adopted Category 2, or InterQual® criteria are met or criteria specified in the Medical Policy Statement Category 4 section of this policy are met for the requested indication for testing. Examples: Below are examples of procedure codes for genetic testing that requires prior authorization when billed with ANY diagnosis code and the prior authorization waiver for pregnant members does NOT apply. This is NOT an all-inclusive list. All Proprietary Laboratory Analysis (PLA) codes are ONLY payable for the Senior Care Options (SCO) product when the test is determined to be medically necessary for the SCO member. S3840 DNA analysis for germline mutations of the RET proto-oncogene for susceptibility to multiple endocrine neoplasia type 2 S3852 DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer’s disease

Category 4: Procedure Codes Considered Experimental and Investigational for All Diagnosis Codes

CPT Codes Description: Codes considered experimental and investigational for all diagnosis codes and plan Medical Director review is required.

All Proprietary Lab Analysis (PLA) codes are ONLY payable for the Senior Care Options (SCO) product when the test is determined to be medically necessary for the SCO member. 0005U Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score

Plan note: This PLA code is billed only when the ExosomeDX test is performed. Code ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0007U Drug test(s), presumptive, with definitive confirmation of positive results, any number of drug classes, urine, includes specimen verification including DNA authentication in comparison to buccal DNA, per date of service

Plan notes: 1. This PLA code is only billed when the ToxProtect test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 2. Review the applicable criteria in the Limitations section of this policy (rather than InterQual® criteria) for the use of genetic testing to confirm the identity of laboratory specimens; e.g., ToxProtect DNA-verified Urine Drug Test (Genotox Laboratories). 0008U Helicobacter pylori detection and antibiotic resistance, DNA, 16S and 23S rRNA, gyrA, pbp1, rdxA and rpoB, next generation sequencing, formalin-fixed paraffin embedded or fresh tissue, predictive, reported as positive or negative for resistance to clarithromycin, fluoroquinolones, metronidazole, amoxicillin, tetracycline and rifabutin

Plan note: This PLA code is only billed when the AmHPR Helicobacter pylori antibiotic resistance next generation sequencing panel is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0010U Infectious disease (bacterial), strain typing by whole genome sequencing, phylogenetic-based report of strain relatedness, per submitted isolate

Plan note: This PLA code is only billed when bacterial typing by whole genome sequencing is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0012U Germline disorders, gene rearrangement detection by whole genome next- generation sequencing, DNA, whole blood, report of specific gene rearrangement(s)

Plan note: This PLA code is only billed when the MatePair, Targeted Rearrangements, Congenital (Mayo Clinic) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0013U Oncology (solid organ neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, fresh or frozen tissue or cells, report of specific gene rearrangement(s)

Plan note: This PLA code is only billed when the MatePair, Targeted Rearrangements, Oncology (Mayo Clinic) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0014M Liver disease, analysis of 3 biomarkers (hyaluronic acid [HA], procollagen III amino terminal peptide [PIIINP], tissue inhibitor of metalloproteinase 1 [TIMP- 1]), using immunoassays, utilizing serum, prognostic algorithm reported as a risk score and risk of liver fibrosis and liver-related clinical events within 5 years 0014U Hematology (hematolymphoid neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood or bone marrow, report of specific gene rearrangement(s)

Plan note: This PLA code is only billed when the MatePair, Targeted Rearrangements, Hematologic (Mayo Clinic) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0015M Adrenal cortical tumor, biochemical assay of 25 steroid markers, utilizing 24- hour urine specimen and clinical parameter, prognostic algorithm reported as a clinical risk and integrated clinical steroid risk for adrena; cortical carcinoma, adenoma, or other adrenal malignancy

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0016M Oncology (bladder) mRNA, microarray gene expression profiling of 209 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as molecular subtype (luminal, luminal infiltrated, basal, basal claudin-low, neiroendocrine-like)

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0017M Oncology (diffuse large B-cell lymphoma [DLBCL]), mRNA, gene expression profiling by fluorescent probe hybridization of 20 genes, formalin-fixed paraffin- embedded tissue, algorithm reported as cell of origin (Do not report 0017M in conjunction with 0120U)

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0018U Oncology (thyroid), microRNA profiling by RT-PCR of 10 microRNA sequences,

Genetic/Genomic Testing and Pharmacogenetics

utilizing fine-needle aspirate, algorithm reported as a positive or negative result for moderate to high risk of malignancy

Plan note: This PLA code is only billed when the ThyraMIR (Interpace Diagnostics) test is performed; the Plan considers ThyraMIR experimental and investigational according to the Limitations section of this policy. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0019U Oncology, RNA, gene expression by whole transcriptome sequencing, formalin- fixed paraffin embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents

Plan note: This PLA codes are only billed when the OncoTarget (Columbia University Department of Pathology and Cell Biology) and OncoTreat (Darwin Health) tests are performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0021U Oncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3-1, 5’-UTR- BMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score

Plan note: This PLA code is only billed when the Apifiny (Armune BioScience, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0067U Oncology (breast), immunohistochemistry, protein expression profiling of 4 biomarkers (matrix metalloproteinase-1 [MMP-1], carcinoembryonic antigen- related cell adhesion molecule 6 [CEACAM6], hyaluronoglucosaminidase [HYAL1], highly expressed in cancer protein [HEC1]), formalin-fixed paraffin- embedded precancerous breast tissue, algorithm reported as carcinoma risk score

Plan note: This PLA code is used to bill for the BBDRisk Dx™ (Silbiotech, Inc.) test. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0069U Oncology (colorectal), microRNA, RT-PCR expression profiling of miR-31-3p, formalin-fixed paraffin-embedded tissue, algorithm reported as an expression score

Plan note: This PLA code is only billed when the miR-31now™ (GoPath Laboratories) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0078U Pain management (opioid-use disorder) genotyping panel, 16 common variants (i.e., ABCB1, COMT, DAT1, DBH, DOR, DRD1, DRD2, DRD4, GABA, GAL, HTR2A, HTTLPR, MTHFR, MUOR, OPRK1, OPRM1), buccal swab or other germline tissue sample, algorithm reported as positive or negative risk of opioid-use disorder

Plan note: This PLA code is only billed when the INFINITI® Neural Response Panel (AutoGenomics Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0080U Oncology (lung), mass spectrometric analysis of galectin-3-binding protein and scavenger receptor cysteine-rich type 1 protein M130, with five clinical risk factors (age, smoking status, nodule diameter, nodule-spiculation status and nodule location), utilizing plasma, algorithm reported as a categorical probability of malignancy

Plan note: This PLA code is only billed when the BDX-XL2 (Biodesix, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0083U Oncology, response to chemotherapy drugs using motility contrast tomography, fresh or frozen tissue, reported as likelihood of sensitivity or resistance to drugs or drug combinations

Plan note: This PLA code is only billed when the Onco4D™ (Animated Dynamics, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0084U Red blood cell antigen typing, DNA, genotyping of 10 blood groups with phenotype prediction of 37 red blood cell antigens

Plan note: This PLA code is only billable when the BLOODchip® ID CORE XT™ (Grifols Diagnostic Solutions Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0085U Cytolethal distending toxin B (CdtB) and vinculin IgG antibodies by immunoassay (i.e., ELISA)

Plan note: This PLA code is only billed when the IBSchek™ (Commonwealth Diagnostics International, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0086U Infectious disease (bacterial and fungal), organism identification, blood culture, using rRNA FISH, 6 or more organism targets, reported as positive or negative with phenotypic minimum inhibitory concentration (MIC)-based antimicrobial susceptibility

Plan note: This PLA code is only billable when the Accelerate PhenoTest™ BC kit (Accelerate Diagnostics, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0087U Cardiology (heart transplant), mRNA gene expression profiling by microarray of 1283 genes, transplant biopsy tissue, allograft rejection and injury algorithm reported as a probability score

Plan note: This PLA code is only billable when the Molecular Microscope® MMDx-Heart (Kashi Clinical Laboratories) test is performed. Code ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0088U Transplantation medicine (kidney allograft rejection), microarray gene expression profiling of 1494 genes, utilizing transplant biopsy tissue, algorithm reported as a probability score for rejection

Plan note: This PLA code is only billable when the Molecular Microscope® MMDx-Kidney (Kashi Clinical Laboratories) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0089U Oncology (melanoma), gene expression profiling by RTqPCR, PRAME and LINC00518, superficial collection using adhesive patch(es)

Plan note: This PLA code is only billable when the Pigmented Lesion Assay (DermTech) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0090U Oncology (cutaneous melanoma), mRNA gene expression profiling by RT-PCR of 23 genes (14 content and 9 housekeeping), utilizing formalin-fixed paraffin- embedded tissue, algorithm reported as a categorical result (i.e., benign, indeterminate, malignant)

Plan note: This PLA code is only billable when the myPath® Melanoma (Myriad Genetic Laboratories) test is performed. Code is ONLY payable for SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0091U Oncology (colorectal) screening, cell enumeration of circulating tumor cells, utilizing whole blood, algorithm, for the presence of adenoma or cancer, reported as a positive or negative result

Plan note: This PLA code is only billable when the FirstSightCRC (CellMax Life) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0092U Oncology (lung), three protein biomarkers, immunoassay using magnetic nanosensor technology, plasma, algorithm, reported as risk score for likelihood of malignancy.

Plan note: This PLA code is only billable when the REVEAL Lung Nodule Characterization (MagArray, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0094U Genome (e.g., unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis

Plan note: This PLA code is only billable when the RCIGM Rapid Whole Genome Sequencing (Rady Children's Institute for Genomic Medicine/RCIGM) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0101U Hereditary colon cancer disorders (e.g., Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (15 genes [sequencing and deletion/duplication], EPCAM and GREM1 [deletion/duplication only])

Plan note: This PLA code is only billable when the ColoNext® (Ambry Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0102U Hereditary breast cancer-related disorders (e.g., hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (17 genes [sequencing and deletion/duplication])

Plan note: This PLA code is only billable when the BreastNext® (Ambry Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0103U Hereditary ovarian cancer (e.g., hereditary ovarian cancer, hereditary

Genetic/Genomic Testing and Pharmacogenetics

endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (24 genes [sequencing and deletion/duplication], EPCAM [deletion/duplication only])

Plan note: This PLA code is only billable when the OvaNext® (Ambry Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0105U Nephrology (chronic kidney disease), multiplex electrochemiluminescent immunoassay (ECLIA) of tumor necrosis factor receptor 1A, receptor superfamily 2 (TNFR1, TNFR2), and kidney injury molecule-1 (KIM-1) combined with longitudinal clinical data, including APOL1 genotype if available, and plasma (isolated fresh or frozen), algorithm reported as probability score for rapid kidney function decline (RKFD)

Plan note: This PLA code is only billable when the KidneyIntelX™ (RenalytixAI) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0108U Gastroenterology (Barrett’s esophagus), whole slide–digital imaging, including morphometric analysis, computer-assisted quantitative immunolabeling of 9 protein biomarkers (p16, AMACR, p53, CD68, COX-2, CD45RO, HIF1a, HER-2, K20) and morphology, formalin-fixed paraffin-embedded tissue, algorithm reported as risk of progression to high-grade dysplasia or cancer

Plan note: This PLA code is only billable when the TissueCypher® Barrett’s Esophagus Assay (Cernostics) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0111U Oncology (colon cancer), targeted KRAS (codons 12, 13, and 61) and NRAS (codons 12, 13, and 61) gene analysis utilizing formalin-fixed paraffin- embedded tissue

Plan note: This PLA code is only billable when the Praxis™ Extended RAS Panel (Illumina) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0112U Infectious agent detection and identification, targeted sequence analysis (16S and 18S rRNA genes) with drug-resistance gene

Plan note: This PLA code is only billable when the MicroGenDX qPCR and NGS for Infection (MicroGenDX) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0113U Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage, by RNA amplification and fluorescence- based detection, algorithm reported as risk score

Plan note: This PLA code is only billable when the MiPS (Mi-Prostate Score by MLabs) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0114U Gastroenterology (Barrett’s esophagus), VIM and CCNA1 methylation analysis, esophageal cells, algorithm reported as likelihood for Barrett’s esophagus

Plan note: This PLA code is only billable when the EsoGuard™ (Lucid Diagnostics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0115U Respiratory infectious agent detection by nucleic acid (DNA and RNA), 18 viral types and subtypes and 2 bacterial targets, amplified probe technique, including multiplex reverse transcription for RNA targets, each analyte reported as detected or not detected

Plan note: This PLA code is only billable when the ePlex Respiratory Pathogen (RP) Panel (GenMark Diagnostics, Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0118U Transplantation medicine, quantification of donor-derived cell-free DNA using whole genome next-generation sequencing, plasma, reported as percentage of donor-derived cell-free DNA in the total cell-free DNA

Plan note: This PLA code is only billable when the Viracor TRAC™ dd-cfDNA (Viracor Eurofins) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0133U Hereditary prostate cancer–related disorders, targeted mRNA sequence analysis panel (11 genes) (List separately in addition to code for primary procedure) (Use 0133U in conjunction with 81162)

Plan note: This PLA code is only billable when the +RNAinsight™ for ProstateNext® (Ambry Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0134U Hereditary pan cancer (e.g., hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (18 genes) (List separately in addition to code for primary procedure) (Use 0134U in conjunction with 81162, 81432, 81435)

Plan note: This PLA code is only billable when the +RNAinsight™ for CancerNext® (Ambry Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0135U Hereditary gynecological cancer (e.g., hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (12 genes) (List separately in addition to code for primary procedure) (Use 0135U in conjunction with 81162)

Plan note: This PLA code is only billable when the +RNAinsight™ for GYNPlus® (Ambry Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0136U ATM (ataxia telangiectasia mutated) (e.g., ataxia telangiectasia) mRNA sequence analysis (List separately in addition to code for primary procedure) (Use 0136U in conjunction with 81408)

Plan note: This PLA code is only billable when the +RNAinsight™ for ATM® (Ambry Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0139U Neurology (autism spectrum disorder [ASD]), quantitative measurements of 6 central carbon metabolites (i.e., a-ketoglutarate, alanine, lactate, phenylalanine, pyruvate, and succinate), LC-MS/MS, plasma, algorithmic analysis with result reported as negative or positive (with metabolic subtypes of ASD)

Plan note: This PLA code is only billable when the NPDX ASD Test (NeuroPointDX) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0153U Oncology (breast), mRNA, gene expression profiling by next-generation

Genetic/Genomic Testing and Pharmacogenetics

sequencing of 101 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a triple negative breast cancer clinical subtype(s) with information on immune cell involvement

Plan note: This PLA code is only billable when the Insight TNBCtype™ (Insight Molecular Labs) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0154U FGFR3 (fibroblast growth factor receptor 3) gene analysis (i.e., p.R248C [c.742C>T], p.S249C [c.746C>G], p.G370C [c.1108G>T], p.Y373C [c.1118A>G], FGFR3-TACC3v1, and FGFR3-TACC3v3)

Plan note: This PLA code is only billable when the therascreen® FGFR RGQ PCR Kit (QIAGEN Manchester Ltd.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0155U PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) (e.g., breast cancer) gene analysis (ie, p.C420R, p.E542K, p.E545A, p.E545D [g.1635G>T only], p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y)

Plan note: This PLA code is only billable when the Therascreen® PIK3CA RGQ Kit (QIAGEN Manchester Ltd.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0156U Copy number (e.g., intellectual disability, dysmorphology), sequence analysis

Plan note: This PLA code is only billable when the SMASH™ test (New York Genome Center) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0163U Oncology (colorectal) screening, biochemical enzyme-linked immunosorbent assay (ELISA) of 3 plasma or serum proteins (teratocarcinoma derived growth factor-1 [TDGF-1, Cripto-1], carcinoembryonic antigen [CEA], extracellular matrix protein [ECM]), with demographic data (age, gender, CRC-screening compliance) using a proprietary algorithm and reported as likelihood of CRC or advanced adenomas

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0164U Gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies, utilizing plasma, algorithm for elevated or not elevated qualitative results

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0166U Liver disease, 10 biochemical assays (?2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, AST, triglycerides, cholesterol, fasting glucose) and biometric and demographic data, utilizing serum, algorithm reported as scores for fibrosis, necroinflammatory activity, and steatosis with a summary interpretation

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0168U Fetal aneuploidy (trisomy 21, 18, and 13) DNA sequence analysis of selected regions using maternal plasma without fetal fraction cutoff, algorithm reported as a risk score for each trisomy

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0169U NUDT15 (nudix hydrolase 15) and TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism) gene analysis, common variants

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0170U Neurology (autism spectrum disorder [ASD]), RNA, next-generation sequencing, saliva, algorithmic analysis, and results reported as predictive probability of ASD diagnosis

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0171U Targeted genomic sequence analysis panel, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, DNA analysis, 23 genes, interrogation for sequence variants, rearrangements and minimal residual disease, reported as presence/absence

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0172U Oncology (solid tumor as indicated by the label), somatic mutation analysis of BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) and analysis of homologous recombination deficiency pathways, DNA, formalin- fixed paraffin-embedded tissue, algorithm quantifying tumor genomic instability score

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0173U Psychiatry (i.e., depression, anxiety), genomic analysis panel, includes variant analysis of 14 genes

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0174U Oncology (solid tumor), mass spectrometric 30 protein targets, formalin-fixed paraffin-embedded tissue, prognostic and predictive algorithm reported as likely, unlikely, or uncertain benefit of 39 chemotherapy and targeted therapeutic oncology agents

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0175U Psychiatry (e.g., depression, anxiety), genomic analysis panel, variant analysis of 15 genes

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0176U Cytolethal distending toxin B (CdtB) and vinculin IgG antibodies by immunoassay (i.e., ELISA)

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0177U Oncology (breast cancer), DNA, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) gene analysis of 11 gene variants utilizing plasma, reported as PIK3CA gene mutation status

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0179U Oncology (non-small cell lung cancer), cell-free DNA, targeted sequence analysis of 23 genes (single nucleotide variations, insertions and deletions, fusions without prior knowledge of partner/breakpoint, copy number variations), with report of significant mutation(s)

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0180U Red cell antigen (ABO blood group) genotyping (ABO), gene analysis Sanger/chain termination/conventional sequencing, ABO (ABO, alpha 1-3-N- acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase) gene, including subtyping, 7 exons

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0181U Red cell antigen (Colton blood group) genotyping (CO), gene analysis, AQP1 (aquaporin 1 [Colton blood group]) exon 1

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0182U Red cell antigen (Cromer blood group) genotyping (CROM), gene analysis, CD55 (CD55 molecule [Cromer blood group]) exons 1-10

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0183U Red cell antigen (Diego blood group) genotyping (DI), gene analysis, SLC4A1 (solute carrier family 4 member 1 [Diego blood group]) exon 19

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0184U Red cell antigen (Dombrock blood group) genotyping (DO), gene analysis, ART4 (ADP-ribosyltransferase 4 [Dombrock blood group]) exon 2

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0185U Red cell antigen (H blood group) genotyping (FUT1), gene analysis, FUT1 (fucosyltransferase 1 [H blood group]) exon 4

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0186U Red cell antigen (H blood group) genotyping (FUT2), gene analysis, FUT2 (fucosyltransferase 2) exon 2

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0187U Red cell antigen (Duffy blood group) genotyping (FY), gene analysis, ACKR1 (atypical chemokine receptor 1 [Duffy blood group]) exons 1-2

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0188U Red cell antigen (Gerbich blood group) genotyping (GE), gene analysis, GYPC (glycophorin C [Gerbich blood group]) exons 1-4

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0189U Red cell antigen (MNS blood group) genotyping (GYPB), gene analysis, GYPB (glycophorin B [MNS blood group]) introns 1, 5, pseudoexon 3

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0190U Red cell antigen (MNS blood group) genotyping (GYPB), gene analysis, GYPB (glycophorin B [MNS blood group]) introns 1, 5, pseudoexon 3

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0191U Red cell antigen (Indian blood group) genotyping (IN), gene analysis, CD44 (CD44 molecule [Indian blood group]) exons 2, 3, 6

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0192U Red cell antigen (Kidd blood group) genotyping (JK), gene analysis, SLC14A1 (solute carrier family 14 member 1 [Kidd blood group]) gene promoter, exon 9

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0193U Red cell antigen (JR blood group) genotyping (JR), gene analysis, ABCG2 (ATP binding cassette subfamily G member 2 [Junior blood group]) exons 2-26

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0194U Red cell antigen (Kell blood group) genotyping (KEL), gene analysis, KEL (Kell metallo-endopeptidase [Kell blood group]) exon 8

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0195U KLF1 (Kruppel-like factor 1), targeted sequencing (i.e., exon 13)

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0196U Red cell antigen (Lutheran blood group) genotyping (LU), gene analysis, BCAM (basal cell adhesion molecule [Lutheran blood group]) exon 3

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0197U Red cell antigen (Landsteiner-Wiener blood group) genotyping (LW), gene analysis, ICAM4 (intercellular adhesion molecule 4 [Landsteiner-Wiener blood group]) exon 1

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0198U Red cell antigen (RH blood group) genotyping (RHD and RHCE), gene analysis Sanger/chain termination/conventional sequencing, RHD (Rh blood group D antigen) exons 1-10 and RHCE (Rh blood group CcEe antigens) exon 5

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0199U Red cell antigen (Scianna blood group) genotyping (SC), gene analysis, ERMAP (erythroblast membrane associated protein [Scianna blood group]) exons 4, 12

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0200U Red cell antigen (Kx blood group) genotyping (XK), gene analysis, XK (X-linked Kx blood group) exons 1-3

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0201U Red cell antigen (Yt blood group) genotyping (YT), gene analysis, ACHE (acetylcholinesterase [Cartwright blood group]) exon 2

Plan note: Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0203U Autoimmune (inflammatory bowel disease), mRNA, gene expression profiling by quantitative RT-PCR, 17 genes (15 target and 2 reference genes), whole blood, reported as a continuous risk score and classification of inflammatory bowel disease aggressiveness

Plan note: This PLA code is only billable when the PredictSURE IBD™ Test (KSL Diagnostics and PredictImmune Ltd.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0204U Oncology (thyroid), mRNA, gene expression analysis of 593 genes (including BRAF, RAS, RET, PAX8, and NTRK) for sequence variants and rearrangements, utilizing fine needle aspirate, reported as detected or not detected

Plan note: This PLA code is only billed when the Afirma Xpression Atlas XA (Veracyte, Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. Review the Limitations section of this policy. 0205U Ophthalmology (age-related macular degeneration), analysis of 3 gene variants (2 CFH gene, 1 ARMS2 gene), using PCR and MALDI-TOF, buccal swab, reported as positive or negative for neovascular age-related macular-degeneration risk associated with zinc supplements

Plan note: This PLA code is only billable when the Vita Risk® test (Artic Medical Laboratories) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. Review the Medical Policy Statement section of this policy. 0206U Neurology (Alzheimer disease); cell aggregation using morphometric imaging and protein kinase C-epsilon (PKCe) concentration in response to amylospheroid treatment by ELISA, cultured skin fibroblasts, each reported as positive or negative for Alzheimer disease

Plan note: This PLA code is only billable when the DISCERN™ test (NeuroDiagnostics) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0207U Quantitative imaging of phosphorylated ERK1 and ERK2 in response to bradykinin treatment by in situ immunofluorescence, using cultured skin fibroblasts, reported as a probability index for Alzheimer disease (List separately in addition to code for primary procedure)

Genetic/Genomic Testing and Pharmacogenetics

0209U Cytogenomic constitutional (genome-wide) analysis, interrogation of genomic regions for copy number, structural changes and areas of homozygosity for chromosomal abnormalities

Plan note: This PLA code is only billable when the CNGnome™ test (PerkinsElmer) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0211U Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association

Plan note: This PLA code is only billable when the MI Cancer Seek™ - NGS Analysis (Caris Life Sciences) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0212U Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband

Plan note: This PLA code is only billable when the Genomic Unity® Whole Genome Analysis - Proband (Variantyx Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0213U Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator genome (e.g., parent, sibling)

Plan note: This PLA code is only billable when the Genomic Unity® Whole Genome Analysis - Comparator (Variantyx Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0214U Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband

Plan note: This PLA code is only billable when the Genomic Unity® Exome Plus Analysis - Proband (Variantyx Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0215U Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator exome (e.g., parent, sibling)

Plan note: This PLA code is only billable when the Genomic Unity® Exome Plus Analysis - Comparator (Variantyx Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0216U Neurology (inherited ataxias), genomic DNA sequence analysis of 12 common genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants

Plan note: This PLA code is only billable when the Genomic Unity® Ataxia Repeat Expansion and Sequence Analysis (Variantyx Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0217U Neurology (inherited ataxias), genomic DNA sequence analysis of 51 genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants

Plan note: This PLA code is only billable when the Genomic Unity® Comprehensive Ataxia Repeat Expansion and Sequence Analysis (Variantyx Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0218U Neurology (muscular dystrophy), DMD gene sequence analysis, including small sequence changes, deletions, duplications, and variants in non-uniquely mappable regions, blood or saliva, identification and characterization of genetic variants

Plan note: This PLA code is only billable when the Genomic Unity® DMD Analysis (Variantyx Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0219U Infectious agent (human immunodeficiency virus), targeted viral next- generation sequence analysis (i.e., protease [PR], reverse transcriptase [RT], integrase [INT]), algorithm reported as prediction of antiviral drug susceptibility

Plan note: This PLA code is only billable when the Sentosa® SQ HIV-1 Genotyping Assay (Vela Diagnostics) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0220U Oncology (breast cancer), image analysis with artificial intelligence assessment of 12 histologic and immunohistochemical features, reported as a recurrence score

Plan note: This PLA code is only billable when the PreciseDx™ Breast Cancer Test (PreciseDx) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0221U Red cell antigen (ABO blood group) genotyping (ABO), gene analysis, next- generation sequencing, ABO (ABO, alpha 1-3-N-acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase) gene

Plan note: This PLA code is only billable when the Navigator ABO Blood Group NGS (Grifols Immunohematology Center) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0222U Red cell antigen (RH blood group) genotyping (RHD and RHCE), gene analysis, next-generation sequencing, RH proximal promoter, exons 1-10, portions of introns 2-3

Plan note: This PLA code is only billable when the Navigator Rh Blood Group NGS (Grifols Immunohematology Center) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0228U Oncology (prostate), multianalyte molecular profile by photometric detection of macromolecules adsorbed on nanosponge array slides with machine learning, utilizing first morning voided urine, algorithm reported as likelihood of prostate cancer 0229U BCAT1 (Branched chain amino acid transaminase 1) or IKZF1 (IKAROS family zinc finger 1) (e.g., colorectal cancer) promoter methylation analysis 0230U AR (androgen receptor) (e.g., spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation), full sequence analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat (STR) expansions, mobile element insertions, and variants in non-uniquely mappable regions 0231U CACNA1A (calcium voltage-gated channel subunit alpha 1A) (e.g., spinocerebellar ataxia), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat (STR) gene expansions, mobile element insertions, and variants in non-uniquely mappable regions 0232U CSTB (cystatin B) (e.g., progressive myoclonic epilepsy type 1A, Unverricht- Lundborg disease), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat (STR) expansions, mobile element insertions, and variants in non-uniquely mappable regions 0233U FXN (frataxin) (e.g., Friedreich ataxia), gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat (STR) expansions, mobile element insertions, and variants in non- uniquely mappable regions 0234U MECP2 (methyl CpG binding protein 2) (e.g., Rett syndrome), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions 0235U PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions 0236U SMN1 (survival of motor neuron 1, telomeric) and SMN2 (survival of motor neuron 2, centromeric) (e.g., spinal muscular atrophy) full gene analysis, including small sequence changes in exonic and intronic regions, duplications and deletions, and mobile element insertions

Genetic/Genomic Testing and Pharmacogenetics

0237U Cardiac ion channelopathies (e.g., Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia), genomic sequence analysis panel including ANK2, CASQ2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, RYR2, and SCN5A, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions 0238U Oncology (Lynch syndrome), genomic DNA sequence analysis of MLH1, MSH2, MSH6, PMS2, and EPCAM, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions 0239U Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free DNA, analysis of 311 or more genes, interrogation for sequence variants, including substitutions, insertions, deletions, select rearrangements, and copy number variations 0242U Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free circulating DNA analysis of 55-74 genes, interrogation for sequence variants, gene copy number amplifications, and gene rearrangements

Plan note: This PLA code is only billed when the Guardant360® CDx (Guardant Health Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0243U Obstetrics (preeclampsia), biochemical assay of placental-growth factor, time- resolved fluorescence immunoassay, maternal serum, predictive algorithm reported as a risk score for preeclampsia

Plan note: This PLA code is only billed when the PlGF Preeclampsia Screen (PerkinElmer Genetics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0244U Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue

Plan note: This PLA code is only billed when the Oncotype MAP™ Pan-Cancer Tissue Test (Paradigm Diagnostics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0245U Oncology (thyroid), mutation analysis of 10 genes and 37 RNA fusions and expression of 4 mRNA markers using next-generation sequencing, fine needle aspirate, report includes associated risk of malignancy expressed as a percentage

Plan note: This PLA code is only billed when the ThyGeNEXT® Thyroid Oncogene Panel (Interpace Diagnostics) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0246U Red blood cell antigen typing, DNA, genotyping of at least 16 blood groups with phenotype prediction of at least 51 red blood cell antigens

Plan note: This PLA code is only billed when the PrecisionBlood™ (San Diego Blood Bank) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0247U Obstetrics (preterm birth), insulin-like growth factor–binding protein 4 (IBP4), sex hormone–binding globulin (SHBG), quantitative measurement by LC- MS/MS, utilizing maternal serum, combined with clinical data, reported as predictive-risk stratification for spontaneous preterm birth

Plan note: This PLA code is only billed when the PreTRM® (Sera Prognostics, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0248U Oncology (brain), spheroid cell culture in a 3D microenvironment, 12 drug panel, tumor-response prediction for each drug

Plan note: This PLA code is only billed when the 3D Predict Glioma (KIYATEC®, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0249U Oncology (breast), semiquantitative analysis of 32 phosphoproteins and protein analytes, includes laser capture microdissection, with algorithmic analysis and interpretative report

Plan note: This PLA code is only billed when the Theralink® Reverse Phase Protein Array/RPPA (Theralink® Technologies, Inc.) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member.

Genetic/Genomic Testing and Pharmacogenetics

0250U Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden

Plan note: This PLA code is only billed when the PGDx elio™ tissue complete (Personal Genome Diagnostics, Inc.) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0251U Hepcidin-25, enzyme-linked immunosorbent assay (ELISA), serum or plasma

Plan note: This PLA code is only billed when the Intrinsic Hepcidin IDx™ Test (Intrinsic LifeSciences, LLC) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0252U Fetal aneuploidy short tandem–repeat comparative analysis, fetal DNA from products of conception, reported as normal (euploidy), monosomy, trisomy, or partial deletion/duplications, mosaicism, and segmental aneuploidy

Plan note: This PLA code is only billed when the POC/Products of Conception test (Igenomix® USA) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0253U Reproductive medicine (endometrial receptivity analysis), RNA gene expression profile, 238 genes by next-generation sequencing, endometrial tissue, predictive algorithm reported as endometrial window of implantation (eg, pre-receptive, receptive, post-receptive)

Plan note: This PLA code is only billed when the ERA® test (Endometrial Receptivity Analysis by Igenomix® USA) is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0254U Reproductive medicine (preimplantation genetic assessment), analysis of 24 chromosomes using embryonic DNA genomic sequence analysis for aneuploidy, and a mitochondrial DNA score in euploid embryos, results reported as normal (euploidy), monosomy, trisomy, or partial deletion/duplications, mosaicism, and segmental aneuploidy, per embryo tested

Plan note: This PLA code is only billed when the SMART PGT-A (Pre- implantation Genetic Testing – Aneuploidy by Igenomix® USA) test is performed. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the SCO member. 0500T Infectious agent detection by nucleic acid (DNA or RNA), human papillomavirus

Genetic/Genomic Testing and Pharmacogenetics

(HPV) for five or more separately reported high-risk HPV types (e.g., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) (i.e., genotyping)

Plan note: See the applicable criteria in the Limitations sections of this policy. Code is ONLY payable for the SCO product when this test is determined to be medically necessary for the member. 81422 Fetal chromosomal microdeletion(s) genomic sequence analysis (e.g., DiGeorge syndrome, Cri-du-chat syndrome), circulating cell-free fetal DNA in maternal blood 81425 Genome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis

Genetic/Genomic Testing and Pharmacogenetics

81427 Genome (e.g., unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained genome sequence (e.g., updated knowledge or unrelated condition/syndrome)

Plan notes: 1. The Plan considers genome sequence analysis to be experimental and investigational when InterQual® criteria are NOT met, as specified in the Limitations section. Plan Medical Director review is required for all prior authorization requests. 2. According to The American College of Obstetricians and Gynecologists (Committee Opinion Number 682), the routine use of whole-genome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published. 81539 Oncology (high-grade prostate cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein-2 [hK2]), utilizing plasma or serum, prognostic algorithm reported as a probability score 81540 Oncology (tumor of unknown origin). mRNA, gene expression profiling by real- time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype

Clinical Background Information Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins and is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Identifying patients who will benefit from certain treatment strategies utilizing pharmacogenetics testing is vital to ensuring better clinical outcomes.

These commercially available, laboratory-developed tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high- complexity testing. The FDA only regulates genetic tests sold as kits and has practiced enforcement discretion for laboratory-developed tests (LDTs), which represent the majority of genetic tests marketed in the United States. While the Centers of Medicare & Medicaid Services (CMS) does regulation the clinical laboratories in which LDTs are performed, CMS does not evaluate whether the genetic tests are clinically meaningful.

Genetic/Genomic Testing and Pharmacogenetics

The American College of Medical Genetics and Genomics (ACMG) does not recommend the self- ordering of direct-to-consumer (DTC) genetic tests by patients without the involvement of a treating healthcare provider. DTC tests might include carrier tests for common genetic diseases, predisposition tests for chronic conditions, and/or pharmacogenetics testing that provides information about how an individual’s genes may response to pharmacotherapy. According to the ACMG, the potential harms include inappropriate test utilization, misinterpretation of test results, lack of necessary follow-up, and other adverse consequences. The accuracy of DTC genetic tests or the reporting of the test results may also be questionable. The Centers for Disease Control and Prevention (CDC) Office of Public Health Genomics (OPHG) supports the process for evaluating scientific data on emerging genetic tests with the ACCE Model Project and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) initiative. Genetic tests and the applications of genomic technology must be evaluated for analytic validity, clinical validity, clinical utility, and associated ethical, legal and social implications.

At the time of the Plan’s most recent policy review, the Centers for Medicare & Medicaid Services (CMS) has implemented national coverage determinations (NCDs) related to genetic tests, including but not limited to the following: NCD for Colorectal Cancer Screening Tests (210.3) for coverage of immunoassay and guaiac fecal occult blood tests and the Cologuard™ - Multitarget Stool DNA (sDNA) test when CMS applicable criteria are met, NCD for Pharmacogenomic Testing for Warfarin Response (90.1) for medically necessary indications for testing as determined by CMS, and NCD for Cytogenetic Studies (190.3) for coverage based on CMS guidelines. CMS has determined that next generation sequencing (NGS) is reasonable and necessary as a diagnostic laboratory test and is covered nationally when performed in a CLIA-certified laboratory, when ordered by a treating physician, and when applicable CMS requirements are met, as specified in the CMS national coverage analysis (NCA) CAG- 00450N. Medicare uses a combination of national and local coverage determinations for making coverage decisions for genetic tests. Medicare administrative contractors (MAC) may implement local coverage determinations (LCDs) that apply only within their own jurisdictions, such as LCD L35000 for Molecular Pathology Procedures. Verify if applicable CMS criteria are in effect (through an NCD, LCD, or other CMS guidelines) for the specified genetic test, product name, site-specific gene analysis, and the indication for testing on the date of the prior authorization request for a Senior Care Options member.

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Agency for Healthcare Research and Quality (AHRQ). U. S. Department of Health & Human Services. Raman G, Avendano EE, Chen M. Technology Assessment Report. Update on Emerging Genetic Tests Currently Available for Clinical Use in Common Cancers. 2013 Jul 19. Accessed at: http://www.cms.gov/Medicare/Coverage/DeterminationProcess/Downloads/id92TA.pdf Genetic/Genomic Testing and Pharmacogenetics

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American College of Medical Genetics and Genomics (ACMG). ACMG Board of Directors. Direct-to- consumer genetic testing: a revised position statement of the ACMGC. Genet Med. 2016 Feb;18(2):207-8. doi: 10.1038/gim.2015.190. Epub 2015 Dec 17. PMID: 26681314.

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Benn P. Non-Invasive Prenatal Testing Using Cell Free DNA in Maternal Plasma: Recent Developments and Future Prospects. J Clin Med. 2014 May 21;3(2):537-65. doi: 10.3390/jcm3020537. Epub 2013 Aug 28. PMID: 23986538.

Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C. Das AF, Craig JA, Chudova DI, Devers PL, Jones KW, Oliver K, Rava RP, Sehnert AJ; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014 Feb 27;370(9):799-808. doi:10.1056/NEJMoa1311037. PMID: 24571752.

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Genetics Home Reference. U.S. National Library of Medicine. CHARGE Syndrome. Accessed at: http://ghr.nlm.nih.gov/condition/charge-syndrome

Genetics Home Reference. U.S. National Library of Medicine. Help Me Understand Genetics. Accessed at: https://ghr.nlm.nih.gov/primer

Genetics Home Reference. U.S. National Library of Medicine. Kabuki syndrome. Accessed at: https://ghr.nlm.nih.gov/condition/kabuki-syndrome

Genetic Home Reference. U.S. National Library of Medicine. What are Single Nucleotide Polymorphisms (SNPs)? Accessed at: https://ghr.nlm.nih.gov/primer/genomicresearch/snp

Genetics Home Reference. U.S. National Library of Medicine. What are the types of genetic tests? Accessed at: https://ghr.nlm.nih.gov/primer/testing/uses

Genetics Home Reference. U.S. National Library of Medicine. What is genetic testing? Accessed at: https://ghr.nlm.nih.gov/primer/testing/genetictesting

Genetic Home Reference. U.S. National Library of Medicine. What is pharmacogenomics? Accessed at: https://ghr.nlm.nih.gov/primer/genomicresearch/pharmacogenomics

Genetic Home Reference. U.S. National Library of Medicine. What are whole exome sequencing and whole genome sequencing? Accessed at: https://ghr.nlm.nih.gov/primer/testing/sequencing

Genetic and Rare Diseases Information Cener. PTEN hamartoma tumor syndrome. Accessed at: https://rarediseases.info.nih.gov/diseases/12800/pten-hamartoma-tumor-syndrome

Han van Krieken J, Kafatos G, Bennett J, Mineur L, Tomášek J, Rouleau E, Fabian P, De Maglio G, García- Alfonso P, Aprile G, Parkar P, Downey G, Demonty G, Trojan J. Panitumumab use in metastatic colorectal cancer and patterns of RAS testing: results from a Europe-wide physician survey and medical records review. BMC Cancer. 2017 Nov 28;17(1):798. doi: 10.1186/s12885-017-3740-4. PMID: 29183279.

Hayes. Clinical Utility Evaluation. Cell-Free DNA (CfDNA) [Formerly NIPS, NIPT] Screening For Fetal Rare Autosomal Trisomies. Dallas, TX: Hayes; 2020 Oct 21.

Hayes. Clinical Utility Evaluation. Clinical Utility of Prenatal Genetic Testing for Autism Spectrum Disorder. Dallas, TX: Hayes; 2018 Sep 28. Annual Review 2020 Jul 30.

Hayes. Clinical Utility Evaluation. Liquid Biopsy Tests for Colorectal Cancer Screening. Dallas, TX: Hayes; 2020 Mar 26.

Genetic/Genomic Testing and Pharmacogenetics

Hayes. Clinical Utility Evaluation. Prenatal and Preimplantation Genetic Testing for Risk of Hearing Loss. Dallas, TX: Hayes; 2019 Dec 11. Annual Review 2020 Nov 18.

Hayes. Clinical Utility Evaluation. Prenatal Whole Genome Sequencing and Prenatal Whole Exome Sequencing. Dallas, TX: Hayes; 2020 Jun 15.

Hayes. Clinical Utility Evaluation. Whole Exome Sequencing For Neurological Conditions In Pediatric Populations. Dallas, TX: Hayes; 2016 Jul 28. Annual Review 2019 Jun 17.

Hayes. Clinical Utility Evaluation. Whole Genome Sequencing (WGS) in Neonatal and Pediatric Patients. Dallas, TX: Hayes; 2016 Sept 22. Annual Review 2019 Aug 12.

Hayes. Clinical Utility Evaluation. Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES) in Patients with Intellectual Disability (ID). Dallas, TX: Hayes; 2021 Jan 21.

Hayes. Molecular Test Assessment. ColonSentry (Stage Zero Life Sciences). Dallas, TX: Hayes; 2020 May 27.

Hayes. Molecular Test Assessment. Epi proColon (Epigenomics Inc.). Dallas, TX: Hayes; 2020 Sep 30.

Hayes. Molecular Test Assessment. Guardant360 (Guardant Health Inc.). Dallas, TX: Hayes; 2018 Dec 11. Annual Review 2020 Aug 10.

Hayes. Molecular Test Assessment. ThyGeNEXT and ThyraMIR (Interpace Diagnostics Group Inc.). Dallas, TX: Hayes; 2019 Jul 10. Annual Review 2020 Jul 19.

Hayes. Molecular Test Assessment. ThyroSeq v3 (University of Pittsburgh Medical Center, CBLPath Inc.). Dallas, TX: Hayes; 2019 May 9. Annual Review 2020 Jun 16.

Hayes News Service. FDA Approves Liquid Biopsy/NGS Diagnostic Test. Dallas, TX: Hayes; 2020 Aug 12.

Hayes. Precision Medicine Insights. Expanded Carrier Screening. Dallas, TX: Hayes; 2020 Aug 17.

Hayes. Precision Medicine Insights. Genetic Testing for Pelizaeus–Merzbacher Disease. Dallas, TX: Hayes; 2020 Oct 22.

Hayes. Precision Medicine Research Brief. Endometrial Receptivity Analysis (Igenomix). Dallas, TX: Hayes; 2017 Aug 10.

Hayes. Precision Medicine Research Brief. Guardant360 (Guardant Health). Dallas, TX: Hayes; 2016 Jun 16.

Genetic/Genomic Testing and Pharmacogenetics

Hayes. Precision Medicine Research Brief. Oncotype MAP Pan-Cancer Tissue Test (Genomic Health Inc.). Dallas, TX: Hayes; 2021 Feb 9.

Hayes. Precision Medicine Research Brief. PreTRM (Sera Prognostics). Dallas, TX: Hayes; 2019 Jul 18.

Hayes. Precision Medicine Research Brief. ThyroSeq V.2 Next Generation Sequencing (CBLPath). Dallas, TX: Hayes; 2016 Oct 13.

Hayes, a TractManager Company. Accessed at: https://evidence.hayesinc.com/

Heart Failure Society of America (HFSA). Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG, Tang WH, Teerlink JR, Walsh MN. Genetic evaluation of cardiomyopathy: HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010 Jun;16(6):e180-94. doi: 10.1016/j.cardfail.2010.04.004. PMID: 20610207.

Heart Rhythm Society (HRS) and European Heart Rhythm Association (EHRA). Ackerman MJ, Silvia GP, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011 Aug;8(8):1308-39. doi: 10.1016/j.hrthm.2011.05.020. PMID: 21787999.

Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA), and Asia Pacific Heart Rhythm Society (APHRS). Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Document endorsed by HRS, EHRA, and APHRS in May 2013 and by the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the Pediatric and Congenital Electrophysiology Society, the Pediatric and Congenital Electrophysiology Society (PACES), and the Association for European Pediatric and Congenital Cardiology (AEPC). Europace. 2013 Oct;15(10):1389-406. doi: 10.1093/europace/eut272. Epub 2013 Aug 30. PMID: 23994779.

Hobson GM, Kamholz J. PLP1-Related Disorders. GeneReviews® [Internet]. Accessed at: http://www.ncbi.nlm.nih.gov/books/NBK1182/

Hong AR, Lim JA, Kim TH, Choi HS, Yoo WS, Min HS, Won JK, Lee KE, Jung KC, Park DJ, Park YJ. The Frequency and Clinical Implications of the BRAF(V600E) Mutation in Papillary Thyroid Cancer Patients in Korea over the Past Two Decades. Endocrinol Metab (Seoul). 2014 Dec 29;29(4):505-13. doi: 10.3803/EnM.2014.29.4.505. Epub 2014 Jul 2. PMID: 25325273.

Genetic/Genomic Testing and Pharmacogenetics

Hung TD, Melnik E, Bogaerts P, Evrard S, Glupczynski Y. Evaluation of the ePlex Blood Culture Identification Panels for Detection of Pathogens in Bloodstream Infections. Journal of Clinical Microbiology. 2019 Feb;57(2):1-11.e01597-18. doi: 10.1128/JCM.01597-18.

Iglesias A, Anyane-Yeboa K, Wynn J, Wilson A, Truitt Cho M, Guzman E, Sisson R, Egan C, Chung WK. The usefulness of whole-exome sequencing in routine clinical practice. Genet Med. 2014 Dec;16(12):922-31. doi: 10.1038/gim.2014.58. Epub 2014 Jun 5. PMID: 24901346.

International Society of Psychiatric Genetics (ISPG). Genetic Testing and Psychiatric Disorders. 2019 Mar 11. Accessed at: https://ispg.net/genetic-testing-statement/

Johansen Taber KA, Dickinson BD, Wilson M. The promise and challenges of next-generation genome sequencing for clinical care. JAMA Intern Med. 2014 Feb 1;174(2):275-80. doi: 10.1001/jamainternmed.2013.12048. PMID: 24217348.

Kagan KO, Sonek J, Wagner P, Hoopmann M. Principles of first trimester screening in the age of noninvasive prenatal diagnosis: screening for chromosomal abnormalities. Arch Gynecol Obstet. 2017 Oct;296(4):645-51. doi: 10.1007/s00404-017-4459-9. Epub 2017 Jul 12. PMID: 28702698.

Kagan KO, Sroka F, Sonek J, Abele H, Lüthgens K, Schmid M, Wagner P, Brucker S, Wallwiener D, Hoopmann M. First-trimester risk assessment based on ultrasound and cell-free DNA vs combined screening: a randomized controlled trial. Ultrasound Obstet Gynecol. 2018 Apr;51(4):437-444. doi: 10.1002/uog.18905. Epub 2018 Mar 4.PMID: 28925570.

Kargi AY, Bustamante MP, Gulec S. Genomic Profiling of Thyroid Nodules: Current Role for ThyroSeq Next-Generation Sequencing on Clinical Decision-Making. Mol Imaging Radionucl Ther. 2017 Feb 9;26(Suppl 1):24-35. doi: 10.4274/2017.26.suppl.04. PMID: 28117287.

Kato S, Schwaederlé C, Fanta PT, Okamura R, Leichman L, Lippman SM, Kurzrock R. Genomic Assessment of Blood-Derived Circulating Tumor DNA in Patients With Colorectal Cancers: Correlation With Tissue Sequencing, Therapeutic Response, and Survival. JCO Precis Oncol. 2019; 3: PO.18.00158. doi: 10.1200/PO.18.00158. PMID: 31032472.

Kirsh KL, Christo PJ, Heit H, Steffel K, Passik SD. Specimen validity testing in urine drug monitoring of medications and illicit drugs: clinical implications. J Opioid Manag. 2015 Jan-Feb;11(1):53-9. doi: 10.5055/jom.2015.0252. PMID: 25750165.

Krane JF, Cibas ES, Alexander EK, Paschke R, Eszlinger M. Molecular analysis of residual ThinPrep material from thyroid FNAs increases diagnostic sensitivity. Cancer Cytopathol. 2015 Jun;123(6):356- 61. doi: 10.1002/cncy.21546. Epub 2015 Apr 29. PMID: 25926393.

Genetic/Genomic Testing and Pharmacogenetics

Lacey S, Chung JY, Lin H. A comparison of whole genome sequencing with exome sequencing for family-based association studies. BMC Proc. 2014 Jun 17;8(Suppl 1 Genetic Analysis Workshop 18Vanessa Olmo):S38. doi: 10.1186/1753-6561-8-S1-S38. eCollection 2014. PMID: 25519383.

Lévesque E, Huang SP, Audet-Walsh E, Lacombe L, Bao BY, Fradet Y, Laverdière I, Rouleau M, Huang CY, Yu CC, Caron P, Guillemette C. Molecular Markers in Key Steroidogenic Pathways, Circulating Steroid Levels, and Prostate Cancer Progression. Clinical Cancer Research. 2013 Feb. doi: 10.1158/1078-0432.CCR-12-2812.

Maortua H, Martínez-Bouzas C, García-Ribes A, Martínez MJ, Guillen E, Domingo MR, Calvo MT, Guitart M, Gabau E, Botella MP, Gener B, Rubio I, López-Aríztegui MA, Tejada MI. MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males). J Mol Diagn. 2013 Sep;15(5):723-9. doi: 10.1016/j.jmoldx.2013.05.002. Epub 2013 Jun 26. PMID: 23810759.

Marberger M, McConnell JD, Fowler I, Andriole GL, Bostwick DG, Somerville MC, Rittmaster RS. Biopsy misidentification identified by DNA profiling in a large multicenter trial. J Clin Oncol. 2011 May 1;29(13):1744-9. doi: 10.1200/JCO.2010.32.1646. Epub 2011 Mar 28. PMID: 21444877.

Marcus FI, Edson S, Towbin JA. Genetics of arrhythmogenic right ventricular cardiomyopathy: a practical guide for physicians. J Am Coll Cardiol. 2013 May 14;61(19):1945-8. doi: 10.1016/j.jacc.2013.01.073. Epub 2013 Mar 14. PMID: 23500315.

Massachusetts Health Quality Partners. Adult Preventive Care Guidelines. 2020.

Matos LL, Trufelli DC, de Matos MG, da Silva Pinhal MA. Immunohistochemistry as an important tool in biomarkers detection and clinical practice. Biomark Insights. 2010 Feb 9;5:9-20. PMID: 20212918.

McCullough RM, Almasri EA, Guan X, Geis JA, Hicks SC, Mazloom AR, Deciu C, Oeth P, Bombard AT, Paxton B, Dharajiya N, Saldivar JS. Non-invasive prenatal chromosomal aneuploidy testing--clinical experience: 100,000 clinical samples. PloS One. 2014 Oct 7;9(10):e109173. doi: 10.1371/journal.pone.0109173. eCollection 2014. PMID: 25289665.

McGregor M, Price TJ. Panitumumab in the treatment of metastatic colorectal cancer, including wild- type RAS, KRAS and NRAS mCRC. Future Oncol. 2018 Oct;14(24):2437-2459. doi: 10.2217/fon-2017- 0711. Epub 2018 May 8. PMID: 29737864.

MedLine Plus. Autosomal dominant. Accessed at: https://medlineplus.gov/ency/article/002049.htm

MedLine Plus. Autosomal recessive. Accessed at: https://medlineplus.gov/ency/article/002052.htm

National Cancer Institute. NCI Dictionary of Cancer Terms. Immunohistochemistry. Accessed at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immunohistochemistry

Genetic/Genomic Testing and Pharmacogenetics

National Cancer Institute. NCI Dictionary of Cancer Terms. Microsatellite Instability. Accessed at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/microsatellite-instability

National Center for Biotechnology Information (NCBI). Genetic Testing Registry (GTR). Human Tests. Accessed at: https://www.ncbi.nlm.nih.gov/gtr/tests/

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Accessed at: https://www.nccn.org/professionals/physician_gls/default.aspx

National Comprehensive Cancer Network (NCCN). NCCN Guidelines®. Accessed at: https://www.nccn.org/professionals/physician_gls/default.aspx

National Comprehensive Cancer Network (NCCN). NCCN Guidelines®. NCCN Guidelines for Detection, Prevention, & Risk Reduction. Accessed at: https://www.nccn.org/professionals/physician_gls/default.aspx#site

National Comprehensive Cancer Network (NCCN). NCCN Guidelines®. NCCN Guidelines for Treatment of Cancer by Site. Accessed at: https://www.nccn.org/professionals/physician_gls/default.aspx#site

National Human Genome Research Institute. National Institutes of Health. Frequently Asked Questions About Genetic Testing. Accessed at: https://www.genome.gov/19516567/faq-about-genetic-testing/

National Human Genome Research Institute. National Institutes of Health. Genetic Testing FAQ. Accessed at: https://www.genome.gov/FAQ/Genetic-Testing

National Human Genome Research Institute. National Institutes of Health. Genomic Education Websites. Accessed at: https://www.genome.gov/about-genomics/teaching-tools/Genomics- Education-Websites

National Human Genome Research Institute. National Institutes of Health. Health Professional Genetics Resources Online. Accessed at: https://www.genome.gov/11510371/health-professional-genetics- resources-online/

National Human Genome Research Institute. National Institutes of Health. Online Genetics Education Resources. Accessed at: https://www.genome.gov/10000464/online-genetics-education-resources/

National Institute for Health and Care Excellence (NICE). NICE Guidance. Accessed at: https://www.nice.org.uk/guidance

National Society of Genetic Counselors (NSGC). NSGC Practice Guidelines. Accessed at: https://www.nsgc.org/practiceguidelines

Genetic/Genomic Testing and Pharmacogenetics

New Hampshire Department of Health and Human Services. Billing Manuals. Accessed at: https://nhmmis.nh.gov/portals/wps/portal/BillingManuals

New Hampshire Department of Health and Human Services. Provider Notices. Accessed at: https://www.dhhs.nh.gov/ombp/pharmacy/notices.htm

Nicholson KJ, Yip L. An update on the status of molecular testing for the indeterminate thyroid nodule and risk stratification of differentiated thyroid cancer. Curr Opin Oncol. 2018 Jan;30(1):8-15. doi: 10.1097/CCO.0000000000000414. PMID: 29028645.

Nikiforova MN, Mercurio S, Wald AI, Barbi de Moura M, Callenberg K, Santana-Santos L, Gooding WE, Yip L, Ferris RL, Nikiforov YE. Analytical performance of the ThyroSeq v3 genomic classifier for cancer diagnosis in thyroid nodules. Cancer. 2018 Apr 15;124(8):1682-90. doi: 10.1002/cncr.31245. Epub 2018 Jan 18. PMID: 29345728.

Nikiforov YE. Role of Molecular Markers in Thyroid Nodule Management: Then and Now. Endocr Pract. 2017 Aug;23(8):979-988. doi: 10.4158/EP171805.RA. Epub 2017 May 23. Review. Erratum in: Endocr Pract. 2017 Nov;23 (11):1362. PMID: 28534687.

Nishino M, Nikiforova M. Update on Molecular Testing for Cytologically Indeterminate Thyroid Nodules. Arch Pathol Lab Med. 2018 Apr;142(4):446-57. doi: 10.5858/arpa.2017-0174-RA. Epub 2018 Jan 16. PMID: 29336606.

Norton ME, Brar H, Weiss J, Karimi A, Laurent LC, Caughey AB, Rodriguez MH, Williams J 3rd, Mitchell ME, Adair CD, Lee H, Jacobsson B, Tomlinson MW, Oepkes D, Hollemon D, Sparks AB, Oliphant A, Song K. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207(2):137.e1-8. doi: 10.1016/j.ajog.2012.05.021. Epub 2012 Jun 1. PMID: 22742782.

Ohori NP, Landau MS, Carty SE, Yip L, LeBeau SO, Manroa P, Seethala RR, Schoedel KE, Nikiforova MN, Nikiforov YE. Benign call rate and molecular test result distribution of ThyroSeq v3. Cancer Cytopathol. 2018 Dec 18. doi: 10.1002/cncy.22088. [Epub ahead of print]. PMID: 30561907.

Onenerk AM, Pusztaszeri MP, Canberk S, Faquin WC. Triage of the indeterminate thyroid aspirate: What are the options for the practicing cytopathologist? Cancer Cytopathol. 2017 Jun;125(S6):477-85. doi: 10.1002/cncy.21828. PMID: 28609009.

Pagan M, Kloos RT, Lin CF, Travers KJ, Matsuzaki H, Tom EY, Kim SY, Wong MG, Stewart AC, Huang J, Walsh PS, Monroe RJ, Kennedy GC. The diagnostic application of RNA sequencing in patients with thyroid cancer: an analysis of 851 variants and 133 fusions in 524 genes. BMC Bioinformatics. 2016 Jan 11;17 Suppl 1:6. doi: 10.1186/s12859-015-0849-9. PMID: 26818556.

Genetic/Genomic Testing and Pharmacogenetics

Partyka KL, Randolph ML, Lawrence KA, Cramer H, Wu HH. Utilization of direct smears of thyroid fine- needle aspirates for ancillary molecular testing: A comparison of two proprietary testing platforms. Diagn Cytopathol. 2018 Apr;46(4):320-5. doi: 10.1002/dc.23902. Epub 2018 Feb 15. PMID: 29446257.

Paschou SA, Vryonidou A, Goulis DG. Thyroid nodules: Α guide to assessment, treatment and follow-up. Maturitas. 2017 Feb;96:1-9. doi: 10.1016/j.maturitas.2016.11.002. Epub 2016 Nov 9. PMID: 28041586.

Patel HH, Goyal N, Goldenberg D. Imaging, genetic testing, and biomarker assessment of follicular cell-derived thyroid cancer. Ann Med. 2014;46(6):409-16.

Pearlstein S, Lahouti AH, Opher E, Nikiforov YE, Kuriloff DB. Thyroseq V3 Molecular Profiling for Tailoring the Surgical Management of Hürthle Cell Neoplasms. Case Rep Endocrinol. 2018 Jul 16;2018:9329035. doi: 10.1155/2018/9329035. eCollection 2018. PMID: 30105107.

Peterson JA, Farland JG, Curtis BR, Aster RH. Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management. Br J Haematol. 2013 Apr;161(1):3–14. doi: 10.1111/bjh.12235. PMID: 23384054.

Pfeifer JD, Liu J. Rate of occult specimen provenance complications in routine clinical practice. Am J Clin Pathol. 2013 Jan;139(1):93-100. doi: 10.1309/AJCP50WEZHWIFCIV. PMID: 23270904.

Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012 Jan 26;483(7387):100-3. doi: 10.1038/nature10868. PMID: 22281684.

Rehm HL, Bale SJ, Bayrak-Toydemir P, Berg JS, Brown KK, Deignan JL, Friez MJ, Funke BH, Hegde MR, Lyon E; Working Group of the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013 Sep;15(9):733-47. doi: 10.1038/gim.2013.92. Epub 2013 Jul 25. PMID: 23887774.

Ross DS. Evaluation and management of thyroid nodules with indeterminate cytology. UpToDate. 2020 May 28.

Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013 May;15(5):399-407. doi: 10.1038/gim.2013.32. Epub 2013 Mar 21. Erratum in: Genet Med. 2013 Aug;15(8):669. PMID: 23519317.

Schwaederle M, Husain H, Fanta PT, Piccioni DE, Kesari S, Schwab RB, Banks KC, Lanman RB, Talasaz A, Parker BA, Kurzrock R. Detection rate of actionable mutations in diverse cancers using a biopsy-free (blood) circulating tumor cell DNA assay. Oncotarget. 2016 Mar 1;7(9):9707-17. doi: 10.18632/oncotarget.7110. PMID: 26848768.

Genetic/Genomic Testing and Pharmacogenetics

Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with Vemurafenib. N Engl J Med. 2012 Feb 23;366(8):707-14. doi: 10.1056/NEJMoa1112302. PMID: 22356324.

Steward DL, Carty SE, Sippel RS, Yang SP, Sosa JA, Sipos JA, Figge JJ, Mandel S, Haugen BR, Burman KD, Baloch ZW, Lloyd RV, Seethala RR, Gooding WE, Chiosea SI, Gomes-Lima C, Ferris RL, Folek JM, Khawaja RA, Kundra P, Loh KS, Marshall CB, Mayson S, McCoy KL, Nga ME, Ngiam KY, Nikiforova MN, Poehls JL, Ringel MD, Yang H, Yip L, Nikiforov YE. Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study. JAMA Oncol. 2018 Nov 8. doi: 10.1001/jamaoncol.2018.4616. [Epub ahead of print.] PMID: 30419129.

Takahama T, Sakai K, Takeda M, Azuma K, Hida T, Hirabayashi M, Oguri T, Tanaka H, Ebi N, Sawa T, Bessho A, Tachihara M, Akamatsu H, Bandoh S, Himeji D, Ohira T, Shimokawa M, Nakanishi Y, Nakagawa K, Nishio K. Detection of the T790M mutation of EGFR in plasma of advanced non-small cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors (west japan oncology group 8014LTR study). Oncotarget. 2016 Sep 6;7(36):58492-9. doi: 10.18632/oncotarget.11303. PMID: 27542267.

ThyroSeq Thyroid Genomic Classifier. Precision Assurance Guidance. Accessed at: https://thyroseq.com/home

ThyroSeq Thyroid Genomic Classifier. Sample Report. Accessed at: https://thyroseq.com/physicians/test-ordering/sample-report

ThyroSeq Thyroid Genomic Classifier. Test Ordering. Accessed at: https://thyroseq.com/physicians/test-ordering/thyroseq

ThyroSeq Thyroid Genomic Classifier. ThyroSeq Test Description. Accessed at: https://thyroseq.com/physicians/test-details/test-description

The University of Michigan Department of Pathology. Clinical Test Catalog. Cytogenetics, Cancer Cytogenomic Array, Tumor. Accessed at: https://www.pathology.med.umich.edu/handbook/#/details/625

University of Washington Laboratory for Precision Diagnostics. Neoplasia Cytogenomic Microarray Analysis. Accessed at: http://uwcpdx.org/neoplasia-microarray-analysis/

Veracyte, Inc. Afirma. What You Should Know. Accessed at: https://www.afirma.com/lp/afirma-what- you-should-know/

Genetic/Genomic Testing and Pharmacogenetics

Wang Z, Andrews P, Kendall J, Ma B, Hakker I, Rodgers L, Ronemus M, Wigler M, Levy D. SMASH, a fragmentation and sequencing method for genomic copy number analysis. Genome Res. 2016 Jun;26(6):844-51. doi: 10.1101/gr.201491.115. Epub 2016 Apr 14. PMID: 27197213.

Winand R, Hens K, Dondorp W, de Wert G, Moreau Y, Vermeesch JR, Liebaers I, Aerts J. In vitro screening of embryos by whole-genome sequencing: now, in the future or never? Hum Reprod. 2014 Apr;29(4):842-51. doi: 10.1093/humrep/deu005. Epub 2014 Feb 2. PMID: 24491297.

Yang Y, Luo X, Yang N, Feng R, Xian L. The prognostic value of excision repair cross-complementation group 1 (ERCC1) in patients with small cell lung cancer (SCLC) receiving platinum-based chemotherapy: evidence from meta-analysis. PLoS One. 2014 Nov 6;9(11):e111651. doi: 10.1371/journal.pone. 0111651. eCollection 2014. PMID: 25375151.

Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013 Oct 17;369(16):1502-11. doi: 10.1056/NEJMoa1306555. Epub 2013 Oct 2. PMID: 24088041.

Zhang M, Lin O. Molecular Testing of Thyroid Nodules: A Review of Current Available Tests for Fine- Needle Aspiration Specimens. Arch Pathol Lab Med. 2016 Dec;140(12):1338-1344. doi: 10.5858/arpa.2016-0100-RA. Epub 2016 Aug 24. PMID: 27557410.

Policy History Original Effective Date* Original Policy Original Approval Date Policy Owner and Version Approved by Number Regulatory Approval: N/A 12/01/11 Medical Policy MPCTAC and QIC Version 1 Manager as Chair Internal Approval: of MPCTAC 08/17/11: Medical Policy, Criteria, and Technology Assessment Committee (MPCTAC) 09/28/11: Quality Improvement Committee (QIC) *Effective Date for the BM HealtNet Plan Commercial Product(s): 01/01/12 *Effective Date for the Well Sense Heath Plan New Hampshire Medicaid Product(s): 01/01/13 *Effective Date for the Senior Care Options Product(s): 01/01/16

Note: Policy title was Genetic Testing Guidelines and Pharmacogenetics until 09/30/18; effective 10/01/18 the policy title has been changed to Genetic/Genomic Testing and Pharmacogenetics.

Genetic/Genomic Testing and Pharmacogenetics

Policy Revisions History Revision Effective Date Review Date Summary of Revisions Approved by and Version Number 07/29/12 Off cycle review for Well Sense Health Version 2 08/03/12: MPCTAC Plan, reformatted Medical Policy 09/13/12: QIC Statement, added Applicable Coding language and code list, deleted references to other products and associated limitations. 09/01/12 Review for effective date 01/01/13. 01/01/13 09/19/12: MPCTAC Added applicable code list, revised Version 3 10/24/12: QIC language in Applicable Coding section, added newborn screening as a type of genetic testing to Description of Item or Service section (from Clinical Background Information section). Added reference to Experimental and Investigational Treatment policy and Medically Necessary policy. Removed duplicate text from Clinical Background Information section. 10/01/13 and Review for effective date 03/01/14. 03/01/14 10/16/13: MPCTAC 11/01/13 Revised Summary, Medical Policy Version 4 11/20/13: MPCTAC Statement, Limitations, Clinical 12/19/13: QIC Background Information, and References sections. Updated list of applicable codes. Summarized CPT code descriptions for CPT codes 81400- 81408 and added Plan note. 01/30/14 Review for effective date 04/01/14. 04/01/14 01/27/14: MPCTAC Added ICD10 diagnosis code Version 5 01/30/14: QIC equivalents of existing ICD9 diagnosis codes. 07/01/14 Review for effective 10/01/14. 10/01/14 07/21/14: MPCTAC Updated Summary section. Added CPT Version 6 (electronic vote) code 81507 and HCPCS code S3870 to 07/24/14: QIC the applicable code list. (electronic vote) 11/01/14 and Review for effective date 03/01/15. 03/01/15 11/19/14: MPCTAC 12/01/14 Revised Summary, Description of Item Version 7 12/02/14: MPCTAC or Service, Definitions, and References (electronic vote) sections. Revised criteria in the 12/10/14: QIC Medical Policy Statement and Limitations section. Updated Genetic/Genomic Testing and Pharmacogenetics

Policy Revisions History applicable code list. 11/25/15 Review for effective date 01/01/16. 01/01/16 11/18/15: MPCTAC Updated template with list of Version 8 11/25/15: MPCTAC applicable products and notes. (electronic vote) Revised language related to applicable 12/09/15: QIC products in the Limitations section without changing criteria. Revised language in the Applicable Coding section. 01/01/16 Review for effective date 05/01/16. 05/01/16 01/20/16: MPCTAC Revised language and list of waived Version 9 02/10/16: QIC pregnancy diagnosis codes and corresponding procedure codes in the Applicable Coding section. Revised list of procedure codes according to industry-standard 2016 code changes. Updated Summary, Description of Item or Service, Definitions, Clinical Background Information, and References sections. Revised criteria in the Medical Policy Statement and Limitations sections. 09/01/16 and Review for effective date 11/01/16. 11/01/16 09/21/16: MPCTAC 09/28/16 Administrative changes made to the Version 10 09/30/16: MPCTAC Summary, Description of Item or (electronic vote) Service, Medical Policy Statement, and 10/12/16: QIC Applicable Coding sections to clarify the types of genetic testing that require Plan prior authorization. No changes made to the criteria and/or the applicable code list. Administrative changes made to clarify language related to gender. Added definitions. 12/05/16 Industry-wide code change with the 01/01/17 Not applicable because addition of 2017 applicable codes Version 11 industry-wide code effective 01/01/17. revisions 01/01/17 Review for effective date 05/01/17. 05/01/17 01/18/17: MPCTAC Revised ICD-10 pregnancy diagnosis Version 12 02/08/17: QIC codes and updated CPT codes in the Applicable Coding section. Updated criteria in the Medical Policy Statement and Limitations sections. Revised Summary, Definitions, Clinical Background Information, References,

Genetic/Genomic Testing and Pharmacogenetics

Policy Revisions History and Reference to Applicable Laws and Regulations sections. Added Plan notes to Applicable Coding section. 06/01/17 Review for effective date 07/01/17. 07/01/17 06/21/17: MPCTAC. Industry-wide code changes made to Version 13 the Applicable Coding section. Administrative changes made to the Summary, Applicable Coding, and References sections. Updated Limitations section to be consistent with industry-wide code addition. 08/09/17 and Revision effective 10/01/17. Industry- 10/01/17 Not applicable because 09/08/17 wide updates to the ICD-10 diagnosis Version 14 CMS industry wide and HCPCS codes included in the changes to HCPCS and Applicable Coding section. ICD10 diagnosis codes 09/20/17 Review for effective date 12/01/17. 12/01/17 09/20/17: MPCTAC Revised criteria in the Limitations Version 15 section. Updated Policy Summary, Description of Item or Service, References, and Other Applicable Policies sections. Revised the applicable code list and administrative changes made to the Applicable Coding section. 12/01/17 Review for effective 01/01/18. 01/01/18 Not applicable because Industry-wide updates to codes Version 16 industry-wide code included in the Applicable Coding changes section. 01/01/18 Review for effective date 04/01/18. 04/01/18 01/17/18: MPCTAC Revised Summary, Definitions, Clinical Version 17 Background Information, and References sections. Updated Medical Policy Statement, Limitations, and Applicable Coding sections. 06/01/18 Review for effective date 09/01/18. 09/01/18 06/20/18: MPCTAC Criteria updated in the Limitations Version 18 section. Administrative change made to the References and Other Applicable Policies sections. 06/25/18 Review for effective date 09/01/18. 09/01/18 06/25/18: MPCTAC Revised criteria in the Medical Policy Version 19 (electronic vote) Statement section. Updated References section. 09/01/18 Review for effective date 10/01/18. 10/01/18 Not applicable because Genetic/Genomic Testing and Pharmacogenetics

Policy Revisions History Revised the policy title. Administrative Version 20 industry-wide code changes made to the Policy Summary, changes Description of Item or Service, Medical Policy Statement, References, and Other Applicable Policies sections. Industry-wide code changes and Plan notes added to Applicable Coding section. 09/19/18 Review for effective date 12/01/18. 12/01/18 09/19/18: MPCTAC Revised criteria in the Limitations Version 21 section. 01/01/19 Review for effective date 04/01/19. 04/01/19 01/16/19: MPCTAC Revised criteria in the Medical Policy Version 22 Statement and Limitations sections. Administrative changes made to the Policy Summary, Definitions, Clinical Background Information, References, Other Applicable Policies, and Reference to Applicable Laws and Regulations sections. Industry-wide code updates and Plan notes revised in the Applicable Coding section. 02/01/19 Review for effective date 05/01/19. 05/01/19 02/20/19: MPCTAC Administrative changes made to the Version 23 Policy Summary, Definitions, References, and Other Applicable Policies sections. Criteria revised in the Medical Policy Statement and Limitations sections. 03/01/19 Review for effective date 05/01/19. 05/01/19 03/20/19: MPCTAC Administrative changes made to the Version 24 Applicable Coding section to be consistent with the criteria revisions approved in version 23. 02/01/19 Review for effective date 06/01/19. 06/01/19 02/20/19: MPCTAC Updated the code list in the Applicable Version 25 Coding section. (formerly Version 24) 03/01/19 Review for effective date 06/01/19. 06/01/19 03/20/19: MPCTAC Administrative changes made to the Version 26 Applicable Coding section to make consistent with the criteria revisions approved in version 23. 06/01/19 Review for effective date 07/01/19. 07/01/19 06/19/19: MPCTAC Administrative changes made to the Version 27

Genetic/Genomic Testing and Pharmacogenetics

Policy Revisions History References and Reference to Applicable Laws and Regulations sections. Industry-wide code additions and Plan notes included in the Applicable Coding section. Revised language in the Policy Summary, Medical Policy Statement, and Applicable Coding section to clarify that the prior authorization waiver for the specified primary pregnancy diagnosis codes only applies to genetic tests ordered, administered, and processed by participating providers and participating laboratories. 07/01/19 Review for effective date 10/01/19. 10/01/19 07/17/19: MPCTAC Adopted InterQual® criteria for genetic Version 28 testing unless specified otherwise in a Plan medical policy. Revised criteria in the Medical Policy Statement and Limitations sections by including medical necessity criteria for genetic testing for indeterminate thyroid nodules and papillary thyroid carcinoma, criteria for targeted genetic testing when indication not specified as medically necessary in Plan-adopted InterQual® criteria or a Plan medical policy, and criteria for multigene panel testing (rather than targeted genetic testing) when Plan-adopted InterQual® criteria are not met or not available. Administrative changes made to the Policy Summary, Description of Item or Service, Definitions, and Other Applicable Policies sections. Maintained diagnosis code list for prior authorization pregnancy waiver and updated applicable procedure code list. 09/01/19 Review for effective 12/01/19. 12/01/19 09/18/19: MPCTAC Updated the list of procedure codes Version 29 and added high-risk diagnosis code in the Applicable coding section. 12/01/19 Review for effective date 01/01/20. 01/01/20 12/18/19: MPCTAC Industry-wide code updates made in Version 30 the Applicable Coding section.

Genetic/Genomic Testing and Pharmacogenetics

Policy Revisions History Administrative changes made to the Policy Summary, Medical Policy Statement, Applicable Coding, Definitions, and References sections. 01/01/20 Review for effective date 04/01/20. 04/01/20 01/15/20: MPCTAC Administrative changes made to the Version 31 Policy Summary, References, and Reference to Applicable Laws and Regulations sections. Plan notes revised in the Applicable Coding section. Criteria revised in the Medical Policy Statement and Limitations sections. 04/01/20 Review for effective date 05/01/20. 05/01/20 04/15/20: MPCTAC Industry-wide code additions and Plan Version 32 notes included in the Applicable Coding section. 06/01/20 Review for effective date 07/01/20. 07/01/20 Not applicable because Industry-wide coding and pertinent Version 33 industry-wide code Plan notes added to the Applicable changes; Coding section. 06/17/20: MPCTAC review 09/01/20 Review for effective date 12/01/20. 12/01/20 09/16/20: MPCTAC Industry-wide coding and pertinent Version 34 Plan notes added to the Applicable Coding section. Plan notes added to the Applicable Coding section. Administrative changes made to the Policy Summary, Description of Item or Service, Clinical Background Information, and References sections. Criteria revised in the Medical Policy Statement and Limitations sections. 12/01/20 Review for effective date 01/01/21. 01/01/21 Not applicable because Industry-wide updates to coding in the Version 35 industry-wide code Applicable Coding section. changes; 12/16/20: MPCTAC review 02/01/21 Review for effective date 06/01/21. 06/01/21 02/17/21: MPCTAC Administrative changes made to the Version 36 Policy Summary, Medical Policy Statement, Limitations, Clinical Not implemented - Background Information, References, replaced with Version and Other Applicable Policies sections. 37

Genetic/Genomic Testing and Pharmacogenetics

Policy Revisions History Code-specific prior authorization requirements revised in the Applicable Coding section. 03/22/21 Review for effective 06/01/21. 06/01/21 Not applicable because Industry-wide updates to coding in the Version 37 industry-wide code Applicable Coding section and revisions changes approved in version 36 implemented. 04/01/21 Review for effective date 07/01/21. 07/01/21 04/21/21: MPCTAC Criteria revised in the Limitation Version 38 section. Plan note added in the Applicable Coding section and updated Not implemented - References section. replaced with Version 39 06/01/21 Review for an effective date 07/01/21. 07/01/21 Not applicable because Industry-wide code updates made in Version 39 industry-wide code the Applicable Coding section. changes; Revisions approved in version 38 06/16/21: MPCTAC implemented. Updated References review section.

Last Review Date 06/01/21

Next Review Date 01/01/22

Authorizing Entity MPCTAC

Other Applicable Policies Administrative Policy - Clinical Review Criteria, policy number OCA 3.201 Administrative Policy - Clinical Technology Evaluation, policy number OCA 3.13 Administrative Policy - Transplantation Administration, policy number OCA 3.10 Medical Policy - Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies, policy number OCA 3.573 Medical Policy - Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances, policy number OCA 3.98 Medical Policy - Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances, policy number OCA 3.99 Genetic/Genomic Testing and Pharmacogenetics

Medical Policy - Experimental and Investigational Treatment, policy number OCA 3.12 Medical Policy - Genetic Testing for Fragile X-Associated Disorders, policy number OCA 3.571 Medical Policy - Genetic Testing for Hereditary Thrombophilia, policy number OCA 3.728 Medical Policy - Infertility Services, policy number OCA 3.725 Medical Policy - Medically Necessary, policy number OCA 3.14 Medical Policy - Preimplantation Genetic Testing, policy number OCA 3.726 Medical Policy - Transplantation of Lung or Lobar Lung, policy number OCA 3.24 Medical Policy - Transplantation of Pancreas or Pancreas-Kidney, policy number OCA 3.25 Medical Policy - Transplantation of Small Bowel, Small Bowel-Liver, or Multivisceral Organs, policy number OCA 3.26 Reimbursement Policy - Drug Screening/Testing (DS/T): Drugs of Abuse, policy number 4.94 Reimbursement Policy - Drug Screening/Testing (DS/T): Drugs of Abuse, policy number WS 4.94 Reimbursement Policy - General Billing and Coding Guidelines, policy number 4.31 Reimbursement Policy - General Billing and Coding Guidelines, policy number SCO 4.31 Reimbursement Policy - General Billing and Coding Guidelines, policy number WS 4.17 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number 4.108 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number SCO 4.108 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number WS 4.18 Reimbursement Policy - Hospital, policy number WS 4.21 Reimbursement Policy - Inpatient Hospital, policy number 4.110 Reimbursement Policy - Inpatient Hospital, policy number SCO 4.110 Reimbursement Policy - Non-Participating Provider, policy number WS 4.5 Reimbursement Policy - Non-Reimbursed Codes, policy number 4.38 Reimbursement Policy - Non-Reimbursed Codes, policy number WS 4.38 Reimbursement Policy - Outpatient Hospital, policy number 4.17 Reimbursement Policy - Outpatient Hospital, policy number SCO 4.17 Reimbursement Policy - Physician and Non-Physician Practitioner Services, policy number 4.608 Reimbursement Policy - Physician and Non-Physician Practitioner Services, policy number SCO 4.608 Reimbursement Policy - Physician and Non-Physician Practitioner Services, policy number WS 4.28 Reimbursement Policy - Provider Preventable Conditions and Serious Reportable Events, policy number 4.610 Reimbursement Policy - Provider Preventable Conditions and Serious Reportable Events, policy number SCO 4.610 Reimbursement Policy - Provider Preventable Conditions and Serious Reportable Events, policy number WS 4.29

Reference to Applicable Laws and Regulations 42 CFR 438.210. Code of Federal Regulations. Title 42 Public Health. Medical Assistance Programs. Managed Care Access Standards. Coverage and Authorization of Services. Genetic/Genomic Testing and Pharmacogenetics

78 FR 48164-69. Federal Register. Centers for Medicare & Medicaid Services (CMS). Medicare Program. Revised Process for Making National Coverage Determinations. 2013 Aug 7.

14.3 CMR 17.00. Code of Massachusetts Regulations. Division of Health Care Finance and Policy. Medicine.

130 CMR. Code of Massachusetts Regulations. Division of Medical Assistance.

Affordable Care Act, 42 USC § 300gg-8.

Commonwealth of Massachusetts. Chapter 207 of the Acts of 2010 - An Act Relative to Insurance Coverage for Autism.

Commonwealth of Massachusetts. General Laws. Accessed at: https://malegislature.gov/Laws/GeneralLaws

Commonwealth of Massachusetts. Massachusetts General Laws Mandating that Certain Health Benefits Be Provided By Commercial Insurers, Blue Cross and Blue Shield and Health Maintenance Organizations. Regulatory Citations. 2017 Oct 24. Accessed at: https://www.mass.gov/files/documents/2017/10/27/mndatben.pdf

Developmental Disabilities Assistance and Bill of Rights Act of 2000, Public Law 106-402.

He-W 500. New Hampshire Code of Administrative Rules. Medical Assistance.

He-W 530.01(e). New Hampshire Code of Administrative Rules. Medical Assistance. Service Limits, Co- Payments, and Non-Covered Services. Definitions. Medically Necessary.

He-W 531. New Hampshire Code of Administrative Rules. Medical Assistance. Physician Services.

He-W 543. New Hampshire Code of Administrative Rules. Medical Assistance. Hospital Services.

MGL c 111 § 70G. Massachusetts General Law. Genetic information and reports protected as private information; prior written consent for genetic testing.

MGL c 1760. Massachusetts General Laws. Health Insurance Consumer Protections.

New Hampshire Department of Health and Human Services (DHHS). Certified Administrative Rules. Accessed at: https://www.dhhs.nh.gov/oos/bhfa/rules.htm

RSA Chapter 326-K. New Hampshire Revised Statutes. Genetic Counselors.

Genetic/Genomic Testing and Pharmacogenetics

RSA Chapter 420-E. New Hampshire Revised Statutes. Insurance. Licensure of Medical Utilization Review Entitles.

Disclaimer Information: + Medical Policies are the Plan’s guidelines for determining the medical necessity of certain services or supplies for purposes of determining coverage. These Policies may also describe when a service or supply is considered experimental or investigational, or cosmetic. In making coverage decisions, the Plan uses these guidelines and other Plan Policies, as well as the Member’s benefit document, and when appropriate, coordinates with the Member’s health care Providers to consider the individual Member’s health care needs. Plan Policies are developed in accordance with applicable state and federal laws and regulations, and accrediting organization standards (including NCQA). Medical Policies are also developed, as appropriate, with consideration of the medical necessity definitions in various Plan products, review of current literature, consultation with practicing Providers in the Plan’s service area who are medical experts in the particular field, and adherence to FDA and other government agency policies. Applicable state or federal mandates, as well as the Member’s benefit document, take precedence over these guidelines. Policies are reviewed and updated on an annual basis, or more frequently as needed. Treating providers are solely responsible for the medical advice and treatment of Members. The use of this Policy is neither a guarantee of payment nor a final prediction of how a specific claim(s) will be adjudicated. Reimbursement is based on many factors, including member eligibility and benefits on the date of service; medical necessity; utilization management guidelines (when applicable); coordination of benefits; adherence with applicable Plan policies and procedures; clinical coding criteria; claim editing logic; and the applicable Plan – Provider agreement.

Genetic/Genomic Testing and Pharmacogenetics