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Hereditary Cancer Syndrome Multigene Panels Lab Management Guidelines V1.0.2020 Hereditary Cancer Syndrome Multigene Panels MOL.TS.182.A v1.0.2020 Introduction Hereditary cancer syndrome multigene panel testing is addressed by this guideline. Procedures addressed The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements. Procedures addressed by this Procedure codes guideline APC Sequencing 81201 APC Deletion/Duplication Analysis 81203 ATM Sequencing 81408 BRCA1/2 Sequencing 81163 BRCA1/2 Deletion/Duplication Analysis 81164 BRCA1 Sequencing 81165 BRCA1 Deletion/Duplication Analysis 81166 BRCA2 Sequencing 81216 BRCA2 Deletion/Duplication Analysis 81167 Chromosomal Microarray [BAC], 81228 Constitutional Chromosomal Microarray [SNP], 81229 Constitutional MLH1 Sequencing 81292 MLH1 Deletion/Duplication Analysis 81294 MSH2 Sequencing 81295 MSH2 Deletion/Duplication Analysis 81297 MSH6 Sequencing 81298 MSH6 Deletion/Duplication Analysis 81300 PALB2 Sequencing 81307 © 2020 eviCore healthcare. All Rights Reserved. 1 of 21 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 Procedures addressed by this Procedure codes guideline PMS2 Sequencing 81317 PMS2 Deletion/Duplication Analysis 81319 PTEN Sequencing 81321 PTEN Deletion/Duplication Analysis 81323 Hereditary breast cancer-related disorders 81432 (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2,CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53 Hereditary breast cancer-related disorders 81433 (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analyses for BRCA1, BRCA2, MLH1, MSH2, and STK11 Hereditary colon cancer disorders (eg, 81435 Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11 Hereditary colon cancer disorders (eg, 81436 Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes, including MLH1, MSH2, EPCAM, SMAD4, and STK11 Hereditary CancerSyndrome © 2020 eviCore healthcare. All Rights Reserved. 2 of 21 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 Procedures addressed by this Procedure codes guideline Hereditary neuroendocrine tumor 81437 disorders (eg, medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); genomic sequence analysis panel, must include sequencing of at least 6 genes, including MAX, SDHB, SDHC, SDHD, TMEM127, and VHL Hereditary neuroendocrine tumor 81438 disorders (eg, medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); duplication/deletion analysis panel, must include analyses for SDHB, SDHC, SDHD, and VHL BRCAplus , Ambry Genetics 0129U BreastNext, Ambry Genetics, Ambry 0102U Genetics ColoNext, Ambry Genetics, Ambry 0101U Genetics OvaNext, Ambry Genetics, Ambry 0103U Genetics Miscellaneous hereditary cancer 81400 syndrome gene tests Miscellaneous hereditary cancer 81401 syndrome gene tests Miscellaneous hereditary cancer 81402 syndrome gene tests Miscellaneous hereditary cancer 81403 syndrome gene tests Miscellaneous hereditary cancer 81404 syndrome gene tests Miscellaneous hereditary cancer 81405 syndrome gene tests Miscellaneous hereditary cancer 81406 syndrome gene tests Miscellaneous hereditary cancer 81407 syndrome gene tests Hereditary CancerSyndrome © 2020 eviCore healthcare. All Rights Reserved. 3 of 21 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 Procedures addressed by this Procedure codes guideline Miscellaneous hereditary cancer 81408 syndrome gene tests Miscellaneous hereditary cancer 81479 syndrome gene tests What are hereditary cancer syndromes Definition A hereditary cancer syndrome is when a mutation in a single gene causes a significantly increased risk for certain cancers. Hereditary cancer syndromes are usually characterized by a pattern of specific cancer types occurring together in the same family, younger ages of cancer diagnosis than usual, or other co-existing non- cancer conditions. Prevalence Most cancer is sporadic and believed to be caused by a mix of behavioral or lifestyle, environmental, and inherited risk factors. However, about 5-10% of cancers are believed to have a major inherited component.1 Hereditary cancer syndromes There are at least 50 hereditary cancer syndromes.1 This table lists some of the most common along with associated cancers.2 Syndrome Associated cancers Hereditary breast and ovarian cancer • breast syndrome (HBOC) • ovarian, fallopian tube, or primary peritoneal cancer • pancreatic • prostate Hereditary CancerSyndrome © 2020 eviCore healthcare. All Rights Reserved. 4 of 21 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 Syndrome Associated cancers Lynch syndrome • colorectal • endometrial • small bowel • stomach • ovarian • pancreatic • ureteral and renal pelvis • biliary tract • brain • sebaceous adenoma • keratoacanthoma tumors Familial adenomatous polyposis • colorectal and other gastrointestinal cancers • gastrointestinal tract polyps such as adenomas and fundic gland • osteomas • desmoids • thyroid cancer • hepatoblastoma MUTYH-associated polyposis • colorectal and other gastrointestinal cancers • adenomas • hyperplastic polyps Cowden syndrome • benign and malignant tumors of the breast, endometrium, and thyroid • cancer and polyps (hamartomas) in the colon and rectum Hereditary CancerSyndrome © 2020 eviCore healthcare. All Rights Reserved. 5 of 21 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 Syndrome Associated cancers Li Fraumeni syndrome • soft tissue sarcoma • osteosarcoma • leukemia • melanoma • breast • pancreas • colon • adrenal cortex • stomach • esophagus • brain Peutz-Jeghers syndrome • polyps (hamartomas) in the stomach • small intestine and colon • pancreas • lung • breast • uterine • ovarian Overlapping clinical findings Many hereditary cancer syndromes can include the same types of cancer and therefore have overlapping clinical findings. For example, breast cancer is a feature of HBOC caused by BRCA mutations, Li Fraumeni syndrome, Cowden syndrome, and others. Sometimes, the pattern of cancers in the family or pathognomonic features makes the underlying syndrome clear. However, in many cases it can be difficult to reliably diagnose hereditary cancer syndromes based on clinical and family history alone. Test information Introduction Testing for hereditary cancer syndromes may include multigene panel testing. Hereditary CancerSyndrome © 2020 eviCore healthcare. All Rights Reserved. 6 of 21 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 Sanger Sequencing Until recently, most sequencing tests used the Sanger sequencing methodology that was originally developed in the 1970s. Sanger sequencing is labor intensive and did not lend itself to high-throughput applications. Next-generation sequencing (NGS) NGS, which is also sometimes called massively parallel sequencing, has been developing since about 2005 to allow larger scale and more efficient gene sequencing. NGS relies on sequencing many copies of small pieces of DNA simultaneously and using bioinformatics to assemble the sequence. The efficiency of NGS has led to an increasing number of large, multi-gene testing panels. NGS panels that test several genes at once are particularly well-suited to conditions caused by more than one gene or where there is considerable clinical overlap between conditions making it difficult to reliably narrow down likely causes. As a result, several laboratories have begun to combine genes involved in causing various hereditary cancer syndromes, which often have both of those characteristics. Detection rate of NGS NGS may not perform as well as Sanger sequencing in some applications. Results may also be obtained that cannot be adequately interpreted based on the current knowledgebase. o When a sequence variation is identified that has not been previously characterized or shown to cause the disorder in question, it is called a variant of uncertain significance (VUS). VUSs are relatively common findings when sequencing large amounts of DNA with NGS. o Under certain circumstances, technologies used in multi-gene testing may fail to identify mutations that might be identifiable through single-gene testing. If high clinical suspicion remains for a particular syndrome after negative multi-gene test results, consultation with the testing lab, additional targeted genetic testing, or both may be warranted. Hereditary cancer syndrome multi-gene panels Hereditary cancer syndrome multi-gene panels include a wide variety of genes and may be focused on the genetic causes of a particular cancer type or broad detection of common hereditary cancer syndromes. Multi-gene
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