Genetic Testing for Hereditary Cancer Form

. Related Medical/Pharmacy Coverage Policies Comparative Genomic Hybridization/Chromosomal Microarray Analysis Genetic Testing Genetic Testing for Breast, Ovarian and Pancreatic Cancer Susceptibility Genetic Testing for Colorectal Cancer Susceptibility Description Genetic testing is a laboratory method that is performed to analyze an individual’s deoxyribonucleic acid (DNA) to detect gene variants (mutations) associated with inherited conditions including hereditary cancer. Approximately 5 to 10 percent of all cancers are hereditary and genetic testing can help determine if a cancer is inherited. This type of testing may also be referred to as germline genetic testing. Testing is available for many cancers including, but not limited to:
• Cutaneous melanoma: A type of skin cancer that is very rarely inherited; most cases occur sporadically. In cases of familial melanoma, an individual may be at increased risk for developing melanoma due to variants in the CDKN2A gene.

Genetic Testing for Hereditary Cancer Page: 2 of 25 • Hereditary diffuse gastric cancer (HDGC): A rare, inherited type of gastric (stomach) cancer that grows in the lining of the stomach and is caused by variants in the CDH1 gene.
• Hereditary neuroendocrine tumor syndromes: A group of rare genetic conditions associated with an increased risk of developing tumors in certain hormone-producing cells within the body known as neuroendocrine cells. These cells are found in several organs such as the adrenal glands, digestive system, pancreas and thyroid. Tumors originating from these cells are referred to as neuroendocrine tumors (NETs). The specific type of NET syndrome varies based on which genes are affected as well as the organs involved. An individual with any of these syndromes may develop more than one tumor during a lifetime, and the tumors may be benign or malignant. The most common syndromes include: o Multiple endocrine neoplasia type 1 (MEN1) is characterized by tumors of the pancreas, parathyroid and pituitary glands and is caused by variants in the MEN1 gene. o Multiple endocrine neoplasia type 2 (MEN2) can cause tumors in the adrenal glands and thyroid due to variants in the RET gene. o Multiple endocrine neoplasia type 4 (MEN4) is similar to the other types of multiple endocrine neoplasia but is caused by variants the CDLN1B gene. An individual with MEN4 can develop tumors in the adrenal, parathyroid and pituitary glands. o Paraganglioma (PGL) and pheochromocytoma (PCC) are related types of rare tumors that form from the same tissue type, arising from neural crest cells. PCC develops specifically in the adrenal glands while PGL arise outside the adrenal glands, often in the abdomen, chest, head, neck or pelvis. Typically, the tumors are benign; however, some tumors can become malignant and metastasize (spread) to other body parts. These tumors can occur sporadically or as part of a hereditary syndrome such as MEN2, MEN4 or von Hippel Lindau syndrome. There are many types of hereditary PGL and PCC, each with its own genetic source, developing in different parts of the body. Variants in several genes are associated with PGL and PCC and include MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD and TMEM127. It may also be appropriate to analyze the RET and VHL genes when certain features of PGL or PCC are present. o von Hippel-Lindau (VHL) syndrome is another rare, inherited disorder characterized by the development of tumors (malignant and benign) in the adrenal glands, brain, eyes, kidneys and pancreas. An individual with VHL has an increased risk of developing clear-cell renal cell carcinoma (ccRCC), a type of kidney cancer. VHL syndrome is caused by variants in the VHL gene. • Retinoblastoma: A cancer that originates in the retina (back of the eye), predominately affecting infants and young children. Although rare, it can occur in adults as well. Retinoblastoma is caused by variants in the RB1 gene.
Multigene panels are defined as a test that analyzes more than one gene simultaneously while single gene testing searches for variants in one specific gene. Multigene panels evaluate the DNA of an individual with a personal and/or family history of a hereditary condition. Pancancer multigene panels analyze genes associated with more than one hereditary cancer syndrome such as breast, colon, ovarian and uterine cancer. Examples of pancancer multigene panels include CancerNext, CancerNext-Expanded and myRisk.

Genetic Testing for Hereditary Cancer Page: 3 of 25 Panels can be targeted or expanded. A targeted panel offers a limited number of genes associated with a specific condition while expanded panels are broad, providing analysis of a large number of genes and often include genes with unclear medical management.
Concurrent (paired) deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) genetic testing (also referred to as expanded RNA analysis) is a laboratory method that analyzes DNA in combination with RNA to purportedly aid with the detection, diagnosis and management of cancer as well as classification of variants of unknown significance (VUS). Paired testing may be offered to an individual who is at increased risk for hereditary cancer and is performed concurrent to DNA testing purportedly to identify additional variants (mutations). +RNAinsight is an example of paired genetic testing and is conducted as an add-on test for multigene hereditary cancer panels such as CancerNext and CancerNext-Expanded. (Refer to Coverage Limitations section) Coverage Determination Any state mandates for genetic testing for hereditary cancer take precedence over this medical coverage policy.
Genetic testing may be excluded by certificate. Please consult the member’s individual certificate regarding Plan coverage.
Apply General Criteria for Genetic and Pharmacogenomics Tests when disease- or gene-specific criteria are not available on a medical coverage policy. For information regarding general criteria for genetic tests, please refer to Genetic Testing Medical Coverage Policy. CUTANEOUS MELANOMA (CDKN2A GENE) Refer to Coverage Limitations section for multigene panel analysis for melanoma. Cutaneous Melanoma – Affected Individual Humana members may be eligible under the Plan for CDKN2A single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for cutaneous melanoma when the following criteria are met: • Pre- and post-test genetic counseling; AND o Individual to be tested has a personal history of 3 or more invasive cutaneous melanomas; OR o Has a personal history of a mix of invasive melanoma, pancreatic cancer and/or astrocytoma; OR o Has a personal history of invasive cutaneous melanoma and has a first-degree relative diagnosed with pancreatic cancer

Cutaneous Melanoma – Unaffected Individual Humana members may be eligible under the Plan for CDKN2A single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for cutaneous melanoma when the following criteria are met: Genetic Testing for Hereditary Cancer Page: 4 of 25 • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-, second- or third-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND o First-, second- and/or third-degree relative (on the same side of the family) has 3 or more invasive cutaneous melanomas; OR o First-, second- and/or third-degree relative (on the same side of the family) has a mix of invasive melanoma, pancreatic cancer and/or astrocytoma Cutaneous Melanoma - Known Familial Pathogenic or Likely Pathogenic Variant Humana members may be eligible under the Plan for cutaneous melanoma KFV genetic testing when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a first-, second- or third-degree relative with a pathogenic or likely pathogenic variant in the CDKN2A gene. Genetic testing should be limited to the KFV. HEREDITARY DIFFUSE GASTRIC CANCER (CDH1 GENE) Refer to Coverage Limitations section for multigene panel analysis for hereditary diffuse gastric cancer (HDGC). HDGC – Affected Individual Humana members may be eligible under the Plan for CDH1 single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for HDGC when the following criteria are met: • Pre- and post-test genetic counseling; AND o Bilateral lobular breast cancer diagnosed before 70 years of age; OR o Diffuse gastric cancer (DGC) diagnosed prior to 50 years of age; OR

Genetic Testing for Hereditary Cancer Page: 5 of 25 o DGC diagnosed at any age and cleft lip/cleft palate; OR o DGC diagnosed at any age and is of Maori ethnicity; OR o DGC and lobular breast cancer, either cancer diagnosed prior to 70 years of age HDGC – Unaffected Individual Humana members may be eligible under the Plan for CDH1 single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for HDGC when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-, second- or third-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND o First-, second- or third-degree relative diagnosed with cleft lip/cleft palate; OR o First-, second- or third-degree relative diagnosed with DGC and lobular breast cancer, either cancer diagnosed before 70 years of age; OR o Two first-, second- or third-degree relatives, on the same side of the family, diagnosed with gastric cancer and one has a confirmed diagnosis of DGC; OR o Two first-, second- or third-degree relatives, on the same side of the family, diagnosed with lobular breast cancer before 50 years of age HDGC - Known Familial Pathogenic or Likely Pathogenic Variant Humana members may be eligible under the Plan for HDGC known familial variant (KFV) genetic testing when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a first- second-or third-degree relative with a pathogenic or likely pathogenic variant in the CDH1 gene. Genetic testing should be limited to the KFV. HEREDITARY NEUROENDOCRINE TUMOR SYNDROMES (CDKN1B, MAX, MEN1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL GENES) Hereditary Neuroendocrine Tumor Syndromes – Affected Individual

Genetic Testing for Hereditary Cancer Page: 6 of 25 Humana members may be eligible under the Plan for multigene panel sequencing (81437) and deletion/duplication analysis (81438) (performed concurrently or sequentially) for hereditary neuroendocrine tumor (NET) syndromes when the following criteria are met: • Pre- and post-test genetic counseling; AND o A mutation identified on tumor genomic testing that has clinical implications if also identified in the germline (eg, tumor analysis shows mutation in BRCA1 or BRCA2 or mismatch repair [MMR] gene); OR o Clinical suspicion for multiple endocrine neoplasia type 1 (MEN1) when either of the following are present:  Personal history of 1 MEN1-related feature and has a first-degree relative diagnosed with at least 1 MEN1-related feature; OR  Personal history of 2 or more MEN1-related features; OR o Clinical suspicion for multiple endocrine neoplasia type 2 (MEN2) due to the presence of medullary thyroid carcinoma (MTC) or other combination of MEN2-related features (eg, pheochromocytoma [PCC], parathyroid adenoma/hyperplasia); OR o Personal history of any of the following:  Adrenocortical carcinoma; OR  Duodenal/pancreatic NET at any age; OR  Gastrinoma (duodenal/pancreatic or type 2 gastric NET); OR  Multifocal pancreatic NETs (PanNETs); OR  Multigland hyperplasia (without obvious secondary causes); OR  Multiple parathyroid adenomas; OR  Paraganglioma (PGL)/PCC; OR  Parathyroid adenoma or primary hyperparathyroidism diagnosed before 30 years of age; OR  Recurrent primary hyperparathyroidism
Hereditary NET Syndromes – Unaffected Individual Humana members may be eligible under the Plan for targeted multigene panel sequencing (81437) and deletion/duplication analysis (81438) (performed concurrently or sequentially) for hereditary NET syndromes when the following criteria are met:

Genetic Testing for Hereditary Cancer Page: 7 of 25 • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND • A first-degree relative with any of the following: o Clinical suspicion for MEN1 when either of the following is present:  Personal history of 1 MEN1-related feature and a first-degree relative diagnosed with at least 1 MEN1-related feature; OR  Personal history of 2 or more MEN1-related features; OR o Clinical suspicion for MEN2 due to the presence of MTC or other combination of MEN2-related features (eg, PCC, parathyroid adenoma/hyperplasia); OR o Personal history of any of the following:  Adrenocortical carcinoma; OR  Duodenal/pancreatic NET at any age; OR  Gastrinoma (duodenal/pancreatic or type 2 gastric NET); OR  Multifocal pancreatic NETs (PanNETs); OR  Multigland hyperplasia (without obvious secondary causes); OR  Multiple parathyroid adenomas; OR  PGL/PCC; OR  Parathyroid adenoma or primary hyperparathyroidism diagnosed before 30 years of age; OR  Recurrent primary hyperparathyroidism
Hereditary NET Syndromes - Known Familial Pathogenic or Likely Pathogenic Variant Humana members may be eligible under the Plan for hereditary NET syndrome KFV genetic testing when the following criteria are met: • Pre- and post-test genetic counseling; AND

Genetic Testing for Hereditary Cancer Page: 8 of 25 • Individual to be tested has a first-degree relative with a pathogenic or likely pathogenic variant in the CDKN1B, MAX, MEN1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL genes. Genetic testing should be limited to the KFV. MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN1 GENE) Multiple Endocrine Neoplasia Type 1 – Affected Individual Humana members may be eligible under the Plan for MEN1 single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for multiple endocrine neoplasia type 1 (MEN1) when the following criteria are met: • Pre- and post-test genetic counseling; AND • Clinical suspicion for MEN1 when either of the following is present: o Personal history of 1 MEN1-related feature and a first-degree relative diagnosed with at least 1 MEN1-related feature; OR o Personal history of 2 or more MEN1-related features MEN1 – Unaffected Individual Humana members may be eligible under the Plan for MEN1 single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for MEN1 when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND • Has a first-degree relative with either of the following: o Personal history of 1 MEN1-related feature and a first-degree relative diagnosed with at least 1 MEN1-related feature; OR o Personal history of 2 or more MEN1-related features MEN1 - Known Familial Pathogenic or Likely Pathogenic Variant

Genetic Testing for Hereditary Cancer Page: 9 of 25 Humana members may be eligible under the Plan for MEN1 KFV genetic testing when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a first-degree relative with a pathogenic or likely pathogenic variant in the MEN1 gene. Genetic testing should be limited to the KFV. MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 (RET GENE) Multiple Endocrine Neoplasia Type 2 – Affected Individual Humana members may be eligible under the Plan for RET single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for multiple endocrine neoplasia type 2 (MEN2) (S3840) when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a personal history at least 1 of the following features of MEN2: o MTC; OR o Parathyroid adenoma or hyperplasia; OR o PCC MEN2 – Unaffected Individual Humana members may be eligible under the Plan for RET single gene sequencing and deletion and duplication analysis (performed concurrently or sequentially) for MEN2 (S3840) when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND • Has a first-degree relative with a confirmed diagnosis of any of the following: o MTC; OR o Parathyroid adenoma or hyperplasia; OR o PCC MEN2 – Known Familial Pathogenic or Likely Pathogenic Variant

Genetic Testing for Hereditary Cancer Page: 10 of 25 Humana members may be eligible under the Plan for RET KFV genetic testing (S3840) when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a first-relative with a pathogenic or likely pathogenic variant in the RET gene. Genetic testing should be limited to the KFV. MULTIPLE ENDOCRINE NEOPLASIA TYPE 4 (CDLN1B GENE) Multiple Endocrine Neoplasia Type 4 – Affected Individual Humana members may be eligible under the Plan for CDLN1B single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for multiple endocrine neoplasia type 4 (MEN4) when the following criteria are met: • Pre- and post-test genetic counseling; AND • Personal history of 1 of the following: o Pancreatic or duodenal NETs; OR o Papillary thyroid carcinoma; OR o Parathyroid adenoma/hyperplasia; OR o Pituitary adenomas MEN4 – Unaffected Individual Humana members may be eligible under the Plan for CDLN1B single gene sequencing and deletion/duplication analysis (performed concurrently or sequentially) for MEN4 when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND • Has a first-degree relative with a personal history of any of the following: o MEN4; OR o Pancreatic or duodenal NETs; OR o Papillary thyroid carcinoma; OR o Parathyroid adenoma/hyperplasia; OR o Pituitary adenomas

Genetic Testing for Hereditary Cancer Page: 11 of 25 MEN4 – Known Familial Pathogenic or Likely Pathogenic Variant Humana members may be eligible under the Plan for CDLN1B KFV genetic testing when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a first-degree relative with pathogenic or likely pathogenic variant in the CDLN1B gene. Genetic testing should be limited to the KFV. RETINOBLASTOMA (RB1 GENE) Retinoblastoma – Affected Individual Refer to Coverage Limitations section for multigene panel analysis for retinoblastoma. Humana members may be eligible under the Plan for RB1 single gene sequencing and deletion/duplication analysis (S3841) (performed concurrently or sequentially) for retinoblastoma when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has been diagnosed with retinoblastoma by ophthalmoscopic examination and confirmed by imaging studies (eg, magnetic resonance imaging [MRI], ocular ultrasonography or optical coherence tomography [OCT]) Retinoblastoma – Unaffected Individual Humana members may be eligible under the Plan for RB1 single gene sequencing and deletion/duplication analysis (S3841) (performed concurrently or sequentially) for retinoblastoma when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-, second- or third-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND • Has a first-degree relative with a confirmed diagnosis of retinoblastoma Retinoblastoma – Known Familial Pathogenic or Likely Pathogenic Variant

Genetic Testing for Hereditary Cancer Page: 12 of 25 Humana members may be eligible under the Plan for RB1 KFV genetic testing (S3841) when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a first-degree relative with a known familial pathogenic or likely pathogenic variant in the RB1 gene. Genetic testing should be limited to the KFV. VON HIPPEL-LINDAU SYNDROME (VHL GENE) Von Hippel-Lindau Syndrome – Affected Individual Humana members may be eligible under the Plan for VHL single gene sequencing and deletion/duplication analysis (S3842) (performed concurrently or sequentially) for von Hippel Lindau (VHL) syndrome when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested exhibits any of the following characteristics of VHL and a clinical diagnosis cannot be established: o Clear cell RCC (ccRCC) diagnosed before 40 years of age; OR o Endolymphatic sac tumor; OR o Hemangioblastoma of the brain, retina or spine; OR o Multiple (more than 1) bilateral ccRCC tumors diagnosed at any age; OR o Multiple (more than 1) pancreatic cysts; OR o Pancreatic NET; OR o Pancreatic serous cystadenoma (more than 1); OR o Papillary cystadenoma of the epididymis or broad ligament; OR
o PCC; OR o PGL of abdomen, neck or thorax; OR o Retinal angioma VHL – Unaffected Individual Humana members may be eligible under the Plan for VHL single gene sequencing and deletion/duplication analysis (S3842) (performed concurrently or sequentially) for VHL when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested is unaffected; AND • An affected first-, second- or third-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND • A first-, second- or third-degree relative has been diagnosed with any of the following:

Genetic Testing for Hereditary Cancer Page: 13 of 25 o Clear cell RCC (ccRCC) diagnosed before 40 years of age; OR o Endolymphatic sac tumor; OR o Hemangioblastoma of the brain, retina or spine; OR o Multiple (more than 1) bilateral ccRCC tumors diagnosed at any age; OR o Multiple (more than 1) pancreatic cysts; OR o Pancreatic NET; OR o Pancreatic serous cystadenoma (more than 1); OR o Papillary cystadenoma of the epididymis or broad ligament; OR o PCC; OR o PGL of abdomen, neck or thorax; OR o Retinal angioma VHL – Known Familial Pathogenic or Likely Pathogenic Variant Humana members may be eligible under the Plan VHL KFV genetic testing (S3842) when the following criteria are met: • Pre- and post-test genetic counseling; AND • Individual to be tested has a first- second-or third-degree relative with a pathogenic or likely pathogenic variant in the VHL gene. Genetic testing should be limited to the KFV. Note: The criteria for genetic testing for hereditary cancer are not consistent with the Medicare National Coverage Policy and therefore may not be applicable to Medicare members. Refer to the CMS website for additional information. Coverage Limitations Humana members may NOT be eligible under the Plan for genetic testing for hereditary cancer for the following: • Deletion/duplication information is obtained as part of the sequencing procedure but submitted as an independent analysis • Individual to be tested has an affected first-, second- or third-degree relative with a negative genetic testing result for the associated condition • Individual to be tested is unaffected and an affected first-, second- or third-degree relative who is available for genetic testing
• KFV analysis using a multigene panel that includes the KFV

Genetic Testing for Hereditary Cancer Page: 14 of 25 • Sequencing, deletion/duplication analysis and large genomic rearrangement analysis of a single gene, multigene panel or sequentially for the detection of a KFV without the KFV results of a relative
These are considered not medically necessary as defined in the member’s individual certificate. Please refer to the member’s individual certificate for the specific definition. Humana members may NOT be eligible under the Plan for genetic testing for hereditary cancer for genes, indications or tests other than those listed above including, but may not be limited to: • Concurrent (paired) DNA and RNA genetic testing (eg, +RNAinsight for CancerNext [0134U]) • Pancancer multigene panels that analyze genes associated with multiple hereditary cancer syndromes including, but may not be limited to: o Ambry Genetics hereditary cancer Next panels including, but may not be limited to:  CancerNext  CancerNext-Expanded  CustomNext-Cancer o BROCA Cancer Risk Panel o Color hereditary cancer panels including, but may not be limited to, Color Extended Hereditary Cancer o Empower Hereditary Cancer Test o Invitae hereditary cancer panels including, but may not be limited to:  Invitae Cancer Screen  Invitae Common Hereditary Cancers Panel  Invitae Multi-Cancer Panel o Myriad myRisk Hereditary Cancer Panel
o myVantage Hereditary Comprehensive Cancer Panel o PreSENTIA Comprehensive Cancer Panel o Preventest o Quest Diagnostics hereditary cancer panels including, but may not be limited to:  Comprehensive Hereditary Cancer Panel  Guideline-Based Hereditary Cancer Panel

Genetic Testing for Hereditary Cancer Page: 15 of 25 o Tempus xG+ o VistaSeq hereditary cancer panels including, but may not be limited to:  Hereditary Cancer Panel  Hereditary Cancer Panel without BRCA • Multigene panel to analyze a single gene including, but may not be limited to:
o CDH1 gene analysis using a multigene panel for the evaluation of gastric cancer o CDKN2A gene analysis using a multigene panel for the evaluation of melanoma o RB1 gene analysis using a multigene panel for the evaluation of retinoblastoma • Multigene panel that includes genes that are not relevant to the individual’s personal and family history These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.