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 such as colorectal cancer (CRC). Testing may be appropriate for affected individuals as well as asymptomatic family members at increased risk for cancer. This type of testing may also be referred to as germline genetic testing. Genetic testing is available for a variety of inherited CRC syndromes which can be categorized as nonpolyposis (absence of polyps) or polyposis (presence of numerous polyps). Affected individuals and unaffected family members are at increased risk for CRC.

These include, but may not be limited to:

• Familial adenomatous polyposis (FAP), also referred to as classic FAP, is a rare, inherited condition caused by a mutation in the APC gene. FAP is characterized by the presence of at least 100 polyps (usually hundreds, sometimes thousands) that develop in the colon and rectum and are highly likely to become cancerous.
• Attenuated familial adenomatous polyposis (AFAP) is a milder form of the condition in which individuals have fewer polyps (less than 100) than those with classic FAP.
• MUTYH-associated polyposis (MAP) is an autosomal recessive polyposis syndrome caused by mutations in the MUTYH gene.
• Cowden syndrome/PTEN hamartoma tumor syndrome is characterized by multiple hamartomas (benign tumor-like growths) which are typically found on the skin and mucous membrane as well as the colon. For information regarding Cowden syndrome/PTEN hamartoma tumor syndrome, please refer to Genetic Testing for Breast, Ovarian and Pancreatic Cancer Susceptibility Medical Coverage Policy.
• Li-Fraumeni syndrome (LFS) is rare and occurs due to TP53 gene variants. Individuals with LFS are at increased risk for developing many types of cancer including CRC. For information regarding LFS, please refer to Genetic Testing for Breast, Ovarian and Pancreatic Cancer Susceptibility Medical Coverage Policy.
• Peutz-Jeghers syndrome (PJS) is characterized by polyps that form in the intestine and dark spots on the mouth and fingers.
• Serrated polyposis syndrome (SPS), formerly known as hyperplastic polyposis, is characterized by the formation of serrated polyps which are a type of growth that sticks out from the surface of the colon or rectum.
• Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is caused by variants in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) and EPCAM gene. This syndrome is associated with an increased risk of developing many types of cancers including colorectal and endometrial (uterine).

Tumor screening and genetic testing assist in determining risk associated with Lynch syndrome. These tests include:

• Immunochemistry (IHC) and/or microsatellite instability (MSI) are screening tests that use colorectal or endometrial tumor specimens to evaluate protein expression of the four MMR genes.

Mutations in these genes are associated with an increased risk of developing a number of cancers. IHC and MSI can be conducted alone, concurrently or sequentially.

• MLH1 promoter methylation testing is performed using tumor tissue to detect hypermethylation of the MLH1 gene promoter, which is common in sporadic microsatellite unstable tumors in CRC and uterine cancers.
• Genetic testing of the MMR genes and the EPCAM gene are pursued when tumor screening results are abnormal or indeterminate.

Multigene (or expanded) panels

analyze a broad set of genes simultaneously (as opposed to single gene testing that searches for variants in one specific gene) and have been proposed to evaluate the DNA of individuals with a personal and/or family history of more than one hereditary condition or syndrome. Panels often include medically actionable genes but may also include those with unclear medical management.

Targeted (or focused) multigene panels

analyze a limited number of genes targeted to a specific condition.

Clinical prediction models

are available to estimate likelihood of an MMR mutation and can assist in the decision to pursue genetic testing for Lynch syndrome. Models are accessible online and use an assortment of information to determine risk including, but not limited to, sex, age at diagnosis of CRC or uterine cancer, family history and specific details about the cancer. Available prediction models include MMRpredict, MMRpro and PREMM5.

For information regarding genetic testing for the following, please refer to Genetic Testing Medical Coverage Policy:

• DNA banking or preservation
• General population screening
• Individual 17 years of age or younger for adult-onset conditions
• Interpretation and reporting for molecular pathology procedure
• Polygenic risk score (PRS) and single nucleotide polymorphisms (SNPs)
• Repeat germline or somatic genetic testing

Genetic Testing for Colorectal Cancer Susceptibility Effective Date: 02/02/2023
Revision Date: 02/02/2023
Review Date: 02/02/2023
Policy Number: HUM-0534-020
Page: 4 of 27

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Retrieved archival tissue

For information regarding array comparative genomic hybridization (aCGH) to detect deletions/duplications and/or for full gene sequence analysis for single gene disorders, please refer to Comparative Genomic Hybridization/Chromosomal Microarray Analysis Medical Coverage Policy.

Coverage Determination

Any state mandates for genetic testing for CRC susceptibility 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.

FAMILIAL ADENOMATOUS AND HAMARTOMATOUS POLYPOSIS SYNDROMES – CORE GENES APC, MUTYH AND STK11

Familial Adenomatous and Hamartomatous Polyposis Syndromes – Affected Individuals

Humana members may be eligible under the Plan for single gene or multigene genomic sequencing and deletion/duplication analysis (performed concurrently or sequentially) for familial adenomatous and hamartomatous polyposis syndromes (FAP, AFAP, MAP, PJS) when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Single gene testing of APC, MUTYH or STK11 genes; OR
• Genomic sequencing and/or deletion/duplication analysis panel (ColoNext [0101U]) that includes the core genes APC, MUTYH and STK11; AND

Individual to be tested has a personal history of any of the following:

• 2 or more histologically confirmed PJS-type hamartomatous polyps; OR
• 2 or more polyps 10 millimeters or more in size; OR
• 5 or more serrated lesions or polyps proximal to the rectum and all polyps 5 millimeters or more in size with at least 2 being at least 10 millimeters; OR
• 10 or more adenomas during the lifetime; OR
• 20 or more serrated lesions or polyps of any size distributed throughout the large bowel, with 5 or more being proximal to the rectum; OR
• Congenital hypertrophy of retinal pigment epithelium (CHRPE) (unilateral, bilateral or multifocal); OR
• Cribriform-morular variant of papillary thyroid cancer; OR
• Desmoid tumor; OR
• Hepatoblastoma; OR
• Perioral or buccal hyperpigmentation; OR

Familial Adenomatous and Hamartomatous Polyposis Syndromes – Unaffected Individuals

Humana members may be eligible under the Plan for single gene or multigene genomic sequencing and deletion/duplication analysis (performed concurrently or sequentially) for familial adenomatous and hamartomatous polyposis syndromes (FAP, AFAP, MAP, PJS) when the following criteria are met:

• Pre- and post-test genetic counseling; AND

Genetic Testing for Colorectal Cancer Susceptibility Effective Date: 02/02/2023
Revision Date: 02/02/2023
Review Date: 02/02/2023
Policy Number: HUM-0534-020
Page: 5 of 27

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Genetic Testing for Colorectal Cancer Susceptibility Effective Date: 02/02/2023
Revision Date: 02/02/2023
Review Date: 02/02/2023
Policy Number: HUM-0534-020
Page: 6 of 27

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• Individual to be tested is unaffected; AND
• Single gene testing of APC, MUTYH or STK11 genes; OR
• Genomic sequencing and/or deletion/duplication analysis panel (ColoNext [0101U]) that includes the core genes APC, MUTYH and STK11; AND
• An affected first-, second- or third-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND
• 18 years of age or older with a sibling diagnosed with MAP; OR
• Family history consistent with autosomal recessive inheritance (affected siblings with unaffected parents); OR
• First-, second- or third-degree relative diagnosed with PJS; OR
• For reproductive purposes when the individual to be tested is of reproductive age and is the reproductive partner of an individual diagnosed with MAP or has an MUTYH variant

Familial Adenomatous and Hamartomatous Polyposis Syndromes – Known Familial Pathogenic or Likely Pathogenic Variant

Humana members may be eligible under the Plan for familial adenomatous and hamartomatous polyposis syndromes KFV genetic testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested has an affected first-, second- or third- degree relative with a pathogenic or likely pathogenic variant. Genetic testing should be limited to the known familial variant (KFV).

LYNCH SYNDROME – TUMOR TESTING

Mismatch Repair by Immunohistochemistry and/or Microsatellite Instability Tumor Testing

Genetic Testing for Colorectal Cancer Susceptibility
Effective Date: 02/02/2023
Revision Date: 02/02/2023
Review Date: 02/02/2023
Policy Number: HUM-0534-020
Page: 7 of 27

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Humana members may be eligible under the Plan for MMR by IHC and/or MSI tumor testing when the individual to be tested is diagnosed with CRC or endometrial cancer.

MLH1 Promoter Methylation Testing

Humana members may be eligible under the Plan for MLH1 promoter methylation testing when the individual to be tested is diagnosed with CRC or endometrial cancer and IHC indicates loss of MLH1 protein expression.

LYNCH SYNDROME – GENETIC TESTING – CORE GENES MLH1, MSH2, MSH6, PMS2 AND EPCAM

Lynch Syndrome – Affected Individual

Humana members may be eligible under the Plan for single gene or multigene genomic sequencing and deletion/duplication analysis (performed concurrently or sequentially) for Lynch syndrome when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Single gene testing of MLH1, MSH2, MSH6, PMS2 or EPCAM genes; OR
• Genomic sequencing and/or deletion/duplication analysis panel (eg, ColoNext [0101U], Genomic Unity Lynch Syndrome Analysis [0238U]) that includes the core genes MLH1, MSH2, MSH6, PMS2 and EPCAM; AND
• Individual to be tested diagnosed with CRC or endometrial cancer; AND
• 2 or more first- or second-degree relatives, on the same side of the family, diagnosed with a Lynch syndrome-related cancer at any age; OR
• Diagnosed before 50 years of age; OR
• Diagnosed with a synchronous (simultaneous) or metachronus (diagnosed at different times) Lynch syndrome-related cancer at any age; OR
• Has a first- or second-degree relative diagnosed with a Lynch syndrome- related cancer before 50 years of age; OR

Genetic Testing for Colorectal Cancer Susceptibility
Effective Date: 02/02/2023
Revision Date: 02/02/2023
Review Date: 02/02/2023
Policy Number: HUM-0534-020
Page: 8 of 27

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• Risk prediction model indicates an increased risk of having an MMR gene pathogenic variant (2.5% or more on PREMM5; 5% or more on MMRpro or MMRpredict); OR
• Individual to be tested diagnosed at any age with an MMR deficient Lynch syndrome-related cancer

Lynch Syndrome – Unaffected Individual

Humana members may be eligible under the Plan for single gene or multigene genomic sequencing and deletion/duplication analysis (performed concurrently or sequentially) for Lynch syndrome when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested is unaffected; AND
  • Single gene testing of MLH1, MSH2, MSH6, PMS2 or EPCAM genes; OR
  • Genomic sequencing and/or deletion/duplication analysis panel (ColoNext [0101U], Genomic Unity Lynch Syndrome Analysis [0238U]) that includes the core genes MLH1, MSH2, MSH6, PMS2 and EPCAM; AND
• An affected first-, second- or third-degree relative is unavailable for genetic testing (eg, deceased, declines genetic testing or unable to contact); AND
• 1 or more first-degree relatives diagnosed with CRC or endometrial cancer AND a synchronous (simultaneous) or metachronous (diagnosed at different times) Lynch syndrome-related cancer at any age; OR
• 1 or more first-degree relatives diagnosed with CRC or endometrial cancer before 50 years of age; OR
• 2 or more first- or second-degree relatives, on the same side of the family, diagnosed with CRC, endometrial cancer or a Lynch syndrome-related cancer, including at least one diagnosed before 50 years of age; OR
• 3 or more first- or second-degree relatives, on the same side of the family, diagnosed with a Lynch syndrome-related cancer, at any age; OR
• Risk prediction model indicates an increased risk of having an MMR gene pathogenic variant (2.5% or more on PREMM5; 5% or more on MMRpro or MMRpredict)

Lynch Syndrome – Known Familial Pathogenic or Likely Pathogenic Variant

Humana members may be eligible under the Plan for Lynch syndrome KFV genetic testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested has an affected first-, second- or third- degree relative with a pathogenic or likely pathogenic variant. Genetic testing should be limited to the KFV.

Coverage Limitations

Humana members may NOT be eligible under the Plan for genetic testing for CRC susceptibility 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
• 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

Genetic Testing for Colorectal Cancer Susceptibility Effective Date: 02/02/2023
Revision Date: 02/02/2023
Review Date: 02/02/2023
Policy Number: HUM-0534-020
Page: 10 of 27

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.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 CRC susceptibility for any indications other than those listed above including, but may not be limited to:

• Ambry Genetics CustomNext + mRNA sequencing analysis for any indication including, but may not be limited to:
  • APC (0157U)
  • Lynch syndrome (0162U)
  • MLH1 (0158U)
  • MSH2 (0159U)
  • MSH6 (0160U)
  • PMS2 (0161U)

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.

Additional information about hereditary CRC syndromes may be found from the following websites:

Background

• American Cancer Society
• Clinical Genome Resource
• National Library of Medicine

Medical Alternatives

Physician consultation is advised to make an informed decision based on an individual's health needs.

Humana may offer a disease management program for this condition. The member may call the number on his/her identification card to ask about our programs to help manage his/her care.

Genetic Testing for Colorectal Cancer Susceptibility Effective Date: 02/02/2023
Revision Date: 02/02/2023
Review Date: 02/02/2023
Policy Number: HUM-0534-020
Page: 11 of 27

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.