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The incidence of CDKN2A mutations in the general population is very low. For example, it is estimated that in Queensland, Australia, an area with a high incidence of melanoma, only 0.2% of all patients with melanoma will harbor a CDKN2A mutation. Mutations are also infrequent in those with an early age onset or those with multiple primary melanomas. However, the incidence of CDKN2A mutations increases with a positive family history; CDKN2A mutations will be found in 5% of families with first degree relatives, rising 20-40% in kindreds with 3 or more affected first degree relatives. Mutation detection rates in the CDK2NA gene is generally estimated as 20-25% in familial cutaneous malignant melanoma (CMM), but can vary between 2% and 50% depending on the family history and population studied.

Familial CMM has been described as a family in which either two first-degree relatives are diagnosed with melanoma, or families with three (3) melanoma patients irrespective of the degree of relationship. Others have defined familial CMM as having at least three (3) (first-, second-, or third-degree) affected members or two (2) affected family members and presence of at least one diagnosed before age 50, or pancreatic cancer in a first- or second-degree relative, or one member with multiple primary melanomas.

Other malignancies associated with familial CMM, specifically those associated with CDKN2A mutations, have been described. The most pronounced associated malignancy is pancreatic cancer, followed by other gastrointestinal malignancies, breast cancer, brain cancer, lymphoproliferative malignancies, and lung cancer. It is also important to recognize that other cancer susceptibility genes may be involved in these families. In particular, germline BRCA2 gene mutations have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer or prostate cancer.

Familial forms of CMM can occur either with or without a family history of multiple dysplastic nevi.  Families with both CMM and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome (FAMMM). This syndrome is difficult to define since there is no agreement on a standard phenotype and dysplastic nevi occur in up to 50% of the general population. Atypical or dysplastic nevi are associated with an increased risk for CMM. Initially, the phenotypes of atypical nevi and CMM were thought to cosegregate in FAMMM families leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that in families with CDKN2A mutations, there were family members with multiple atypical nevi who were non-carriers of the CDKN2A familial mutation. Thus, the nevus phenotype cannot be used to distinguish carriers from non-carriers of CMM susceptibility in these families.

Some common allele(s) are associated with increased susceptibility to CMM but have low penetrance. One such gene is the Melanocortin 1 receptor gene (MC1R). Variants in this gene are relatively common and have low penetrance for CMM. This gene is associated with fair complexion, freckles and red hair; all risk factors for CMM. Variants in MC1R also modify the CMM risk in families with CDKN2A mutations.

Melaris® is a commercially available genetic test of the CDKN2A gene.

None

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

There are no specific CPT codes for genetic testing specifically for susceptibility to malignant melanoma. A series of CPT codes describing the individual steps in the genetic analysis would be used.

6/20/2007: Policy reviewed, description updated to include FAMMM and hereditary risk for melanoma versus increased susceptibility. Policy statement updated to include hereditary melanoma. "Mutations Associated with Malignant Melanoma Susceptibility" replaced with "Cutaneous Malignant Melanoma" in policy title

8/18/2008: Policy reviewed, no changes

10/21/2010: Policy reviewed; no changes.

12/13/2011:  Added “Familial” to the policy title.  Replaced "hereditary" with "familial" in the policy statement and throughout the policy.

11/28/2012: Policy reviewed; no changes.

All codes billed for this procedure are considered investigational and not eligible for coverage. 

Non-Covered Codes

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