APC Testing
Genetic testing of the APC gene may be considered medically necessary in the following individuals :
At-risk relatives (see Policy Guidelines section) of patients with familial adenomatous polyposis (FAP) and/or a known APC variant.
Individuals with a differential diagnosis of attenuated FAP versus MUTYH-associated polyposis (MAP) versus Lynch syndrome. Whether testing begins with APC variants or screening for mismatch repair (MMR) variants depends on clinical presentation.
Genetic testing for APC gene variants is investigational for colorectal cancer (CRC) patients with classical FAP for confirmation of the FAP diagnosis.
Testing for germline APC gene variants for inherited CRC syndromes is considered investigational in all other situations.
MUTYH Testing
Genetic testing of the MUTYH gene may be considered medically necessary in the following patients:
Patients with a differential diagnosis of attenuated FAP versus MAP versus Lynch syndrome and a negative result for APC gene variants. A family history of no parents or children with FAP is consistent with MAP (autosomal recessive).
Testing for germline MUTYH gene variants for inherited CRC syndromes is considered investigational in all other situations.
MMR Gene Testing
Genetic testing of MMR genes (MLH1, MSH2, MSH6, PMS2) may be considered medically necessary in the following patients:
Individuals with CRC with tumor testing suggesting germline MMR deficiency or meeting clinical criteria for Lynch syndrome (see Policy Guidelines section).
Individuals with endometrial cancer with tumor testing suggesting germline MMR deficiency or meeting clinical criteria for Lynch syndrome (see Policy Guidelines section).
At-risk relatives (see Policy Guidelines section) of individuals with Lynch syndrome with a known pathogenic/likely pathogenic MMR gene variant.
Individuals with a differential diagnosis of attenuated FAP versus MAP versus Lynch syndrome. Whether testing begins with APC variants or screening for MMR genes depends on clinical presentation.
Individuals without CRC but with a family history meeting the Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a validated risk prediction model (e.g. MMRpro, PREMM5 or MMRpredict), when no affected family members have been tested for MMR variants
Testing for germline MMR gene variants for inherited CRC syndromes is considered investigational in all other situations.
EPCAM Testing
Genetic testing of the EPCAM gene may be considered medically necessary when any 1 of the following 3 major criteria (solid bullets) is met:
Individuals with CRC, for the diagnosis of Lynch syndrome (see Policy Guidelines section) when:
Tumor tissue shows lack of MSH2 protein expression by immunohistochemistry and individual is negative for an MSH2 germline variant; OR
Tumor tissue shows a high level of microsatellite instability and individual is negative for a germline variant in MLH1, MSH2, MSH6, and PMS2; OR
At-risk relatives (see Policy Guidelines section) of individuals with Lynch syndrome with a known pathogenic/likely pathogenic EPCAM variant; OR
Individuals without CRC but with a family history meeting the Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a validated risk prediction model (e.g. MMRpro, PREMM5 or MMRpredict), when no affected family members have been tested for MMR variants, and when sequencing for MMR variants is negative.
Testing for germline EPCAM gene variants for inherited CRC syndromes is considered investigational in all other situations.
BRAF V600E or MLH1 promoter methylation
Somatic genetic testing for BRAF V600E or MLH1 promoter methylation may be considered medically necessary to exclude a diagnosis of Lynch syndrome when the MLH1 protein is not expressed in a CRC tumor on immunohistochemical analysis.
Testing for somatic BRAF V600E or MLH1 promoter methylation to exclude a diagnosis of Lynch syndrome is considered investigational in all other situations.
SMAD4 and BMPR1A Testing
Genetic testing of SMAD4 and BMPR1A genes may be considered medically necessary when any 1 of the following major criteria (solid bullets) is met:
Individuals with a clinical diagnosis of juvenile polyposis syndrome based on the presence of any 1 of the following:
at least 5 juvenile polyps in the colon
multiple juvenile polyps found throughout the gastrointestinal tract
any number of juvenile polyps in a person with a known family history of juvenile polyps.
At-risk relative of a patient suspected of or diagnosed with juvenile polyposis syndrome.
Testing for germline SMAD4 and BMPR1A gene variants for inherited CRC syndromes is considered investigational in all other situations.
STK11 Testing
Genetic testing for STK11 gene variants may be considered medically necessary when any 1 of the following major criteria (solid bullets) is met:
Individuals with a clinical diagnosis of Peutz-Jeghers syndrome based on the presence of any 2 of the following:
presence of 2 or more histologically confirmed Peutz-Jeghers polyps of the gastrointestinal tract.
characteristic mucocutaneous pigmentation of the mouth, lips, nose, eyes, genitalia, or fingers
family history of Peutz-Jeghers syndrome.
At-risk relative of anindividual suspected of or diagnosed with Peutz-Jeghers syndrome.
Testing for germline STK11 gene variants for inherited CRC syndromes is considered investigational in all other situations.
Other Variants
Genetic testing of all other genes for an inherited CRC syndrome is considered investigational.
Genetic Counseling
Pre- and post-test genetic counseling may be considered medically necessary as an adjunct to the genetic testing itself.
