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Hereditary (Germline) Testing After Tumor (Somatic) Testing Lab Management Guidelines v2.0.2019 Hereditary (Germline) Testing After Tumor (Somatic) Testing MOL.CU.246.A v2.0.2019 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 BRCA1/2 185delAG, 5385insC, 617delT 81212 variants BRCA1/2 Known Familial Variants 81215 Chromosomal Microarray [BAC], 81228 Constitutional Chromosomal Microarray [SNP], 81229 Constitutional MLH1 Sequencing 81292 MLH1 Deletion/Duplication Analysis 81294 MLH1 Known Familial Variants 81293 MSH2 Sequencing 81295 MSH2 Deletion/Duplication Analysis 81297 MSH2 Known Familial Variants 81296 MSH6 Sequencing 81298 MSH6 Deletion/Duplication Analysis 81300 © eviCore healthcare. All Rights Reserved. 1 of 8 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines v2.0.2019 Procedures addressed by this Procedure codes guideline MSH6 Known Familial Variants 81299 PMS2 Sequencing 81317 PMS2 Deletion/Duplication Analysis 81319 PTEN Sequencing 81321 PTEN Deletion/Duplication Analysis 81323 PTEN Known Familial Variants 81326 Hereditary breast cancer-related disorders 81432 (e.g., hereditary breast cancer, hereditary r ovarian cancer, hereditary endometrial o cancer); genomic sequence analysis panel, must include sequencing of at least m 10 genes, including BRCA1, BRCA2, u T CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53 r e Hereditary breast cancer-related disorders 81433 t (e.g., hereditary breast cancer, hereditary f A ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis g panel, must include analyses for BRCA1, n BRCA2, MLH1, MSH2, and STK11 i t Hereditary colon cancer disorders (e.g., 81435 s Lynch syndrome, PTEN hamartoma e syndrome, Cowden syndrome, familial T adenomatosis polyposis); genomic ) sequence analysis panel, must include e sequencing of at least 10 genes, including n i APC, BMPR1A, CDH1, MLH1, MSH2, l MSH6, MUTYH, PTEN, SMAD4, and m STK11 r Hereditary colon cancer disorders (e.g., 81436 e Lynch syndrome, PTEN hamartoma G ( syndrome, Cowden syndrome, familial adenomatosis polyposis); y duplication/deletion analysis panel, must r a include analysis of at least 5 genes, t including MLH1, MSH2, EPCAM, SMAD4, i and STK11 d e r e H © eviCore healthcare. All Rights Reserved. 2 of 8 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines v2.0.2019 Procedures addressed by this Procedure codes guideline Hereditary neuroendocrine tumor 81437 disorders (e.g., 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 (e.g., medullary thyroid r carcinoma, parathyroid carcinoma, o malignant pheochromocytoma or paraganglioma); duplication/deletion m analysis panel, must include analyses for u SDHB, SDHC, SDHD, and VHL T Miscellaneous hereditary cancer 81400 r e syndrome gene tests t f Miscellaneous hereditary cancer 81401 A syndrome gene tests Miscellaneous hereditary cancer 81402 g n syndrome gene tests i t Miscellaneous hereditary cancer 81403 s syndrome gene tests e T Miscellaneous hereditary cancer 81404 syndrome gene tests ) e Miscellaneous hereditary cancer 81405 n syndrome gene tests i l Miscellaneous hereditary cancer 81406 m syndrome gene tests r Miscellaneous hereditary cancer 81407 e syndrome gene tests G ( Miscellaneous hereditary cancer 81408 syndrome gene tests y r Miscellaneous hereditary cancer 81479 a t syndrome gene tests i d e r e H © eviCore healthcare. All Rights Reserved. 3 of 8 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines v2.0.2019 What is germline hereditary cancer testing following somatic tumor testing Definition Most cancer is sporadic and due to the acquisition of somatic variants. In addition, about 5-10% of cancer has a hereditary etiology due to constitutional germline variants.1 In oncology, next generation sequencing (NGS) technology makes it feasible to catalog the DNA sequence variations within a person’s cancer (i.e., somatic mutation profiling). This helps define therapeutic targets which might improve outcomes through the use of specific medications directed at those mutations.2 Germline variants can also be identified as an ancillary finding during primary tumor profiling to identify somatic mutations. “In the course of analyzing tumor DNA (without matched normal DNA), sequencing can identify potential constitutional (germline) DNA variations that are associated with disease or susceptibility to g disease as well as carrier states for Mendelian disorders. Centers may use n i matched tumor-normal sequencing to facilitate more accurate calling of somatic t mutations by using the normal DNA to exclude germline variants from the tumor s cells.” 3,4 e T o In a study by Schrader et al, “Targeted tumor sequencing with a panel of 341 r genes and matched normal DNA in 1566 individuals with advanced malignant o neoplasms revealed presumed pathogenic germline variants (PPGVs) in about 16% of individuals. Most PPGVs (80.5%, 95% CI, 75.1%-85.0%) were in genes m related to cancer susceptibility. The PPGVs in genes previously designated as u clinically actionable cancer targets were seen in 5.0% (95% CI, 4.1%-6.2%) of T individuals. Most cancer-susceptibility PPGVs were retained in the tumor r 5 (91.9%; 95% CI, 87.3%-95.0%). This study is in line with other published e t studies investigating the prevalence of incidental findings with somatic tumor f profiling.” 4,6 A The debate continues regarding whether there is an obligation to test for and report these germline findings which are secondary to the original purpose of somatic g n tumor profiling. In making this determination, pre-test informed consent is of utmost i importance. “Honoring patient preferences requires oncology providers to t communicate the potential for incidental and secondary germline information s specific to the test being offered, the relevance and potential benefits of this e T information for patients and their relatives, and the limitations and risks of receiving 2 incidental and secondary germline information.” y r a t Test information i d Testing to investigate somatic and constitutional DNA variants has become more e r common as sequencing technology has evolved from the more labor intensive e Sanger sequencing to NGS. “NGS is a powerful technology that permits the H © eviCore healthcare. All Rights Reserved. 4 of 8 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines v2.0.2019 characterization of large amounts of DNA sequence much quicker and at lower cost than traditional Sanger sequencing.” 2,7 Laboratories performing somatic mutation profiling may include paired germline testing, not in an effort to identify hereditary etiologies but to identify variants that are genetic “drivers” of the individual’s malignancy.4 Laboratories may also use bioinformatics to subtract the inherited variants from the somatic tumor profiling findings. Germline variants may be missed during this process without performing further analysis.8,9 Guidelines and evidence The National Comprehensive Cancer Network (NCCN, 2017)10 states the following regarding germline testing following somatic tumor testing for BRCA1/2 mutations. o BRCA1/2 germline mutation testing should be considered when a BRCA1/2 g mutation is detected by tumor profiling on any tumor type. n i There have been various peer-reviewed publications that reviewed pre- and post- t s test considerations for germline testing following somatic tumor testing. e T o Pre-test considerations: r . Somatic tumor-only NGS testing is used to guide treatment for an affected o person. The testing is not designed to elucidate a hereditary etiology. A m germline variant may not be detected (due to differences in coverage in the u testing, cellularity of the sample, allelic loss of the germline mutation) or may T not be reported by the somatic testing laboratory.2,3,11 r . Directed germline genetic testing can be ordered to identify a potential e t hereditary etiology for the person’s tumor. Referrals to oncology genetic f counselors or other specialized healthcare providers should occur if the A individual’s personal and/or family history meets established criteria to warrant a more detailed discussion.10,12,13 g n . Ancillary findings from somatic or germline testing may include variants in i t genes that cause a hereditary cancer syndrome, a non-oncologic hereditary s syndrome, or identify carrier status for Mendelian disease. Specific findings e 2,3,11 are dependent on specific testing performed by the laboratory. T . Many patients undergoing somatic tumor profiling have advanced stage y disease. Centers performing somatic tumor profiling should consider r a obtaining a surrogate individual to receive results in the event that the t proband has passed away or
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