Coverage Policy Manual
Policy #: 2004043
Category: Laboratory
Initiated: July 2004
Last Review: September 2018
  Genetic Test: Melanoma, Hereditary

A genetic predisposition to cutaneous malignant melanoma is suspected in specific clinical situations: 1) melanoma has been diagnosed in multiple family members; 2) multiple primary melanomas are identified in a single patient; and 3) when there is an early age of onset. A positive family history of melanoma is the most significant risk factor; it is estimated that approximately 10% of melanoma cases report a first- or second-degree relative with melanoma. While some of the familial risk may be related to shared environmental factors, 3 main genes involved in cutaneous malignant melanoma susceptibility have now been identified. CDKN2A, located on chromosome 9p21 encodes proteins that act as tumor suppressors. Mutations at this site can alter the tumor suppressor function. The second gene, CDK4, is an oncogene located on chromosome 12q13, and has been identified in about 6 families worldwide. A third gene, not fully characterized, maps to chromosome 1p22.
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 of onset or those with multiple primary melanomas (Hayward 2003). 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 to 20%–40% in kindreds with 3 or more affected first-degree relatives (Kefford et al, 1999). Mutation detection rates in the CDK2NA gene is generally estimated as 20%–25% in hereditary CMM, but can vary between 2% and 50% depending on the family history and population studied.
Hereditary cutaneous malignant melanoma (CMM) has been described as a family in which either 2 first-degree relatives are diagnosed with melanoma or a family with 3 melanoma patients irrespective of the degree of relationship. (de Snoo et al, 2003). Others have defined hereditary CMM as having at least 3 (first-, second- or third-degree) affected members, or 2 affected family members in which at least 1 was diagnosed before age 50 years or pancreatic cancer occurred in a first- or second-degree relative, or 1 member had multiple primary melanomas (Casula et al, 2007).
Other malignancies associated with hereditary 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.
Hereditary 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 (Pho et al, 2006).
Melaris® is a commercially available genetic test of the CDKN2A gene.
Effective in 2013, there is CPT coding to more specifically report CDKN2A testing. Code 81404 includes:
CDKN2A (cyclin-dependent kinase inhibitor 2A) (e.g., CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence
Prior to 2013, there were 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 have been used.

Genetic testing for mutations associated with hereditary cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is a screening procedure. Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures).
For members with contracts where the above situations do not apply, genetic testing for mutations associated with hereditary cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.  
For members with contracts without Primary Coverage Criteria, where the above situations do not apply, genetic testing for mutations associated with hereditary cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.  Investigational services are exclusions in the member benefit certificate of coverage.

Validation of the clinical use of any diagnostic test focuses on 3 main principles: 1) analytic validity of the test; i.e., the technical performance of the test; 2) clinical validity, i.e., the diagnostic performance of the test, such as sensitivity, specificity, and positive and negative predictive values in different populations of patients and compared to the gold standard; and 3) clinical utility of the test, i.e., how the results of the diagnostic test will be used to improve patient management.
Analytic Validity
Genetic testing typically consists of sequence analysis of the coding regions and intron/exon splice sites or analysis of a specific mutation. Studies report identifying deleterious mutations in the 5' untranslated region and deep intronic mutations in the CDKN2A gene.
Clinical Validity
The clinical validity is related to the interpretation of the results of the genetic analysis for the individual patient. One issue common to genetic testing for any type of cancer susceptibility is determining the clinical significance of individual mutations. For example, mutations in the CDKN2A gene can occur along its entire length, and some of these mutations represent harmless polymorphisms or noncoding mutations. Interpretation will improve as more data accumulate regarding the clinical significance of individual mutations in families with a known hereditary pattern of melanoma. However, the penetrance of a given mutation will also affect its clinical significance, particularly since the penetrance of CDKN2A mutations may vary with ethnicity and geographic location (Hayward, 2003; Kefford, 1999).  For example, exposure to sun and other environmental factors, as well as behavior and ethnicity may contribute to the penetrance. Bishop and colleagues have estimated that the calculated risk of developing melanoma before age 80 years in carriers of CDKN2A mutations ranges from 58% in Europe to 91% in Australia (Bishop, 2002).  
Interpretation of a negative test is another issue. CDKN2A mutations are found in less than half of those with strong family history of melanoma. Therefore, additional melanoma predisposition genes are likely to exist, and patients with a strong family history with normal test results must not be falsely reassured that they are not at increased risk (Hayward, 2003). For example, in a 2011 meta-analysis of 145 genome-wide association studies, 8 independent, genetic loci were identified as being associated with a statistically significant risk of cutaneous melanoma, including 6 with strong epidemiological credibility (MC1R, TYR, TYRP1, SLC45A2, ASIP/PIGU/MYH7B, and CDKN2A/MTAP) (Chatzinasiou, 2011). Also, in a 2011 meta-analysis of 20 studies with data from 25 populations, red hair color variants on the MC1R gene were associated with the highest risk of melanoma but non-red hair color variants were also associated with an increased risk of melanoma. (8) In a 2012 review, Ward and colleagues noted the genetics of melanoma are far from being understood, and “it is likely a large number of SNPs (single nucleotide proteins), each with a small effect and low penetrance, in addition to the small number of large effect, high-penetrance SNPs, are responsible for CMM (cutaneous malignant melanoma) risk (Ward, 2012).”
In 2009, Yang and colleagues conducted a study to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations (Yang, 2009). The investigators genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A-positive, 9 CDKN2A-negative) for genes involved in DNA repair, apoptosis, and immune response. Their analyses identified some candidate genes, such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9, and JAK3, that were associated with CMM risk; after correction for multiple comparisons, IL9 remained significant. The effects of some genes were stronger in CDKN2A-positive families (BCL7A and IL9), while some were stronger in CDKN2A-negative families (BCL2L1). The authors concluded that these findings support the hypothesis that common genetic polymorphisms in DNA repair, apoptosis, and immune response pathways may modify the risk of CMM in CMM-prone families, with or without CDKN2A mutations.
In 2010, Kanetsty and colleagues conducted a study to describe associations of MC1R (melanocortin 1 receptor gene) variants and melanoma in a U.S. population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure (Kanetsky, 2010). The study population included melanoma patients (n=960) and controls (n=396), with self-reported phenotypic characteristics and sun exposure information. Logistic regression was used to estimate associations of high- and low-risk MC1R variants and melanoma, overall and within phenotypic and sun exposure groups. Carriage of 2 low-risk, or any high risk MC1R variants, was associated with increased risk of melanoma (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.0-2.8; and OR: 2.2; 95% CI: 1.5-3.0, respectively). However, risk was noted to be stronger in or limited to individuals with protective phenotypes and limited sun exposure, such as those who tanned well after repeated sun exposure (OR: 2.4), had dark hair (OR: 2.4), or had dark eyes (OR: 3.2). The authors concluded that these findings indicate MC1R genotypes provide information about melanoma risk in those individuals who would not be identified as high-risk based on their phenotypes or exposures alone. However, how this information impacts patient care and clinical outcomes is not known.
A 2010 article on identifying individuals at high risk for melanoma emphasizes the use of the family history (Psaty, 2010).
Clinical Implications
While genetic testing for CDKN2A mutations is recognized as an important research tool, its clinical use will depend on how the results of the genetic analysis can be used to improve patient management. Currently, management of patients considered at high risk for malignant melanoma focuses on reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. (See policy No. 2003021 for further discussion of dermatoscopy and related techniques for skin surveillance.) At present, it is unclear how genetic testing for CDKN2A would alter these management recommendations. The following clinical situations can be considered:
1. Affected individual with a positive family history
If an affected individual tests positive for a CDKN2A mutation, he/she may be at increased risk for a second primary melanoma compared to the general population. However, limited and protected sun exposure and increased surveillance would be recommended to any patient with a malignant melanoma, regardless of the presence of a CDKN2A mutation. However, a positive result will establish a mutation, thus permitting targeted testing for the rest of the family. In addition, a positive mutation in an affected family member increases the likelihood of its clinical significance if detected in another family member. As described, a negative test is not interpretable.
2. Unaffected individual in a high-risk family
If the unaffected individual is the first to be tested in the family (i.e., no affected relative has been previously tested to define the target mutation), it is very difficult to interpret the clinical significance of a mutation, as described. The likelihood of clinical significance is increased if the identified mutation is the same as one reported in other families, although the issue of penetrance is a confounding factor. If the unaffected individual has the same mutation as an affected relative, then the patient is at high risk for melanoma. However, again it is unclear how this would affect the management of the patient. Increased sun protection and surveillance are recommended for any patient in a high-risk family.
The published data on genetic testing of the CDKN2A and CDK4 genes focus on the underlying genetics of hereditary melanoma, identification of mutations in families at high risk of melanoma, and risk of melanoma in those harboring these mutations. Other studies have also focused on the association between CDKN2A and pancreatic cancer (Puig, 2005; Rulyak, 2003; Rutter, 2004). One publication added the caution that differences in melanoma risk across geographic regions justify the need for studies in individual countries before counseling should be considered (Goldstein, 2007).  
In a 2008 study, Aspinwall et al. found short-term change in behavior among a small group of patients without melanoma who were positive for the CDKN2A mutation (Aspinwall, 2008). In this prospective study of 59 members of a CDKN2A mutation-positive pedigree, behavioral assessments were made at baseline, immediately after CDKN2A test reporting and counseling, and at 1-month follow-up (42 participants). Across multiple measures, test reporting caused CDKN2A mutation carriers without a melanoma history to improve to the level of adherence reported by participants with a melanoma history. CDKN2A-positive participants without a melanoma history reported greater intention to obtain total body skin examinations, increased intentions and adherence to skin self-examination recommendations, and increased number of body sites examined at 1 month.
In a 2011 retrospective case-control study, van der Rhee and colleagues sought to determine whether a surveillance program of families with CDKN2A mutations allowed for earlier identification of melanomas (van der Rhee, 2011). Characteristics of 40 melanomas identified in 35 unscreened patients (before heredity was diagnosed) were compared to 226 melanomas identified in 92 relatives of those 35 unscreened melanoma patients that were found to have the CDKN2A mutation and participated in a surveillance program over a 25-year period. Surveillance consisted of a minimum of an annual total skin evaluation, which became more frequent if melanoma was diagnosed. Melanomas diagnosed during surveillance were found to have a significantly lower Breslow thickness (median thickness 0.50 mm) than the melanomas identified in the unscreened patients (median thickness 0.98 mm), signifying earlier identification with surveillance. However, only 53% of melanomas identified in the surveillance group were detected on regular screening appointments. Additionally, there was no correlation between length of screening intervals (for intervals less than 24 months) and melanoma tumor thickness at time of diagnosis. The authors also noted that despite understanding the importance of surveillance, patient noncompliance was still observed in the surveillance program, and almost half of patients were noncompliant when first diagnosed with melanoma.
Branstrom and colleagues examined a self-reported survey of genetic testing perceptions and preventive behaviors in 312 family members with increased risk of melanoma. Fifty-three percent had been diagnosed with melanoma, and 12% had a positive susceptibility genetic test (Branstrom, 2012). The study indicated that a negative test might be associated with an erroneous perception of lower risk and fewer preventive measures.
Ongoing Clinical Trials
A search of online site identified one observational study, sponsored by the National Cancer Institute, to identify genetic and environmental factors related to melanoma risk in individuals and families at high risk for melanoma (NCT00040352). Another study to develop a model for genetic susceptibility for melanoma is active but no longer recruiting patients (NCT00591500).
Because some cases of cutaneous malignant melanoma (CMM) are familial, potential genetic markers for this disease are being evaluated. Some of these markers are being evaluated in those with a family history of disease; other markers are being evaluated to estimate risk of CMM in those who may not have a family history.
The evidence to date is insufficient to permit conclusions concerning the effect of genetic testing for melanoma on health outcomes. While research continues in this area, none of the articles identified demonstrate how the presence or absence of these genetic mutations would impact clinical care—either for those with melanoma or for those at risk due to a family history. The changes in patient management that result from finding a mutation in a patient at risk are not known. In addition, not finding a mutation does not exclude the presence of familial cutaneous malignant melanoma. The conclusion concerning unknown impact on outcomes applies to both mutations with high penetrance (CDKN2A), as well as those with low penetrance (MC1R), which may increase susceptibility.
Practice Guidelines and Position Statements
The Melanoma Genetics Consortium, comprising familial melanoma researchers from North America, Europe, and Australia, indicated, in 2002, that genetic testing for melanoma susceptibility should not be offered outside of a research setting (Kefford, 2002).  
In 2002, in an American Society of Clinical Oncology (ASCO) publication, Kefford noted the sensitivity and specificity of tests for CDKN2A mutations are not fully known (Kefford, 2002). Because interpreting genetic tests is difficult and because test results do not alter patient management, the Kefford publication indicated CDKN2A genetic testing should be performed only in clinical trials for several reasons including: a low likelihood of finding mutations in known melanoma susceptibility genes, uncertainty about the functionality and phenotypic expression of the trait among mutation carriers, and the lack of proven melanoma prevention and surveillance strategies. Additionally, it was noted all patients with risk factors for cutaneous melanoma should follow programs of sun protection and skin surveillance, not just those patients considered to be high risk due to family history.
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search was conducted through August 2017. There was no new published studies identified that would prompt a change in the coverage statement.
In 2016, Di Lorenzo et al published a study on 400 patients with CMM who were observed for a 6-year period at an Italian university (Di Lorenzo, 2016). Forty-eight patients met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 variants. Genetic testing revealed that none of the families carried variants in the CDK4 gene and only 1 patient harbored the rare CDKN2A p.R87W variant. The study did not identify a high variant rate of CDKN2A in patients affected by familial melanoma or multiple melanomas. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate-/low-penetrance susceptibility genes, which, together with environmental factors (eg, latitude, sun exposure), could determine the occurrence of melanoma.
2018 Update
A literature search was conducted through August 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
Borroni et al evaluated asymptomatic individuals with family members diagnosed with primary cutaneous melanoma (PCM) and a CDKN2A variant who underwent genetic testing and counseling (Borroni, 2017).  Of the 19 unrelated patients with PCM and a CDKN2A variant, 40 clinically healthy relatives were tested. Fifteen of the 40 relatives tested positive for the same variant as the relative with PCM. The 15 relatives underwent a complete dermatologic examination with dermoscopy. During a mean follow-up of 37 months (range, 4-53 months), none of the relatives developed PCM.
The American Academy of Dermatology published guidelines on the management of primary cutaneous melanoma (AAD, 2011). The use of genetic testing in patients diagnosed with cutaneous malignant melanoma or asymptomatic patients with family history of the disease was not addressed.


References: American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility. J Clin Oncology 2003; 21.

Aspinwal LG, Leaf SL, Dola ER et al.(2008) CDKN2A/p16 genetic test reporting improves early detection intenetions and practices in high-risk melanoma families. Cancer Epidemiol Biomarkers Prev 2008; 17(6):15110-1519.

Bichakjian CK, Halpern AC, Johnson TM, et al.(2011) Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol. Nov 2011;65(5):1032-1047. PMID 21868127

Bishop DT, Demenais F, Goldstein AM et al.(2002) Geographic variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 2002; 94(12):894-903.

Borroni RG, Manganoni AM, Grassi S, et al.(2017) Genetic counselling and high-penetrance susceptibility gene analysis reveal the novel CDKN2A p.D84V (c.251A>T) mutation in melanoma-prone families from Italy. Melanoma Res. Apr 2017;27(2):97-103. PMID 28060055

Branstrom R, Kasparian NA, Affleck P et al.(2012) Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma. Eur J Cancer 2012.

Casula M., Colombino M, Satta MP et al.(2007) Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy. Eur J Cancer 2007;43(1):137-143.

Chatzinasiou F, Lill CM, Kypreou K et al.(2011) Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. J Natl Cancer Inst 2011; 103(16):1227-35.

de Snoo FA, Bergman W, Gruis NA.(2003) Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer 2003; 2(2):109-116.

Di Lorenzo S, Fanale D, Corradino B, et al.(2016) Absence of germline CDKN2A mutation in Sicilian patients with familial malignant melanoma: Could it be a population-specific genetic signature? Cancer Biol Ther. 2016;17(1):83-90. PMID 26650572

Goldstein AM, Chaudru V, Ghiorzo P et al.(2007) Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mitation carriers from 4 countries. Int J Cancer 2007; 121(4):825-831.

Hansen CB, Wadge LM, Lowstuter K, et al.(2004) Clinical germ-line genetic testing for melanoma. Lancet 2004; 5:314-319.

Hayward NK.(2003) Genetics of melanoma predisposition. Oncogene 2003; 22(20):3053-3062.

Kanetsky PA, Panossian S, Elder DE et al.(2010) Does MC1R genotype convey information about melanoma risk beyond risk phenotypes? Cancer 2010; 116(10):2416-28.

Kefford R, Bishop JN, Tucker M et al.(2002) Genetic testing for melanoma. Lancet Oncol 2002;3(11):653-654.

Kefford RF, Newton-Bishop JA, Bergman W et al.(1999) Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 1999;17(10):3245-51.

Pho L, Grossman D, Leachman SA.(2006) Nelanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma. Curr Opin Oncol 2006; 18(2):173-179.

Psaty EL, Scope A, Halpern AC et al.(2010) Defining the patient at high risk for melanoma. Int J Dermatol 2010; 49(4):362-76.

Puig S, Mallvehy J, Badenas C et al.(2005) Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol 2005;23(13):3043-3051.

Rulyak SJ, Brentnall TA, Lynch HT et al.(2003) Characterization of the neoplastic phenotype in the familial atypical multiple-mole melanoma-pancreatic carcinoma syndrome. Cancer 2003;98(4):798-804.

Rutter JL, Bromley CM, Goldstein AM et al.(2004) Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study. Cancer 2004; 101(12):2809-2816.

Tsao H, Atkins MB, Sober AJ.(2004) Management of cutaneous melanoma. NEJM 2004; 351:998-1012.

van der Rhee JI, de Snoo FA, Vasen HF et al.(2011) Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families. J Am Acad Dermatol 2011; 65(2):289-96.

Ward KA, Lazovich D, Hordinsky MK.(2012) Germline melanoma susceptibility and prognostic genes: A review of the literature. J Am Acad Dermatol 2012.

Williams PF, Olsen CM, Hayward NK et al.(2011) Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. Int J Cancer 2011; 129(7):1730-40.

Yang XR, Pfeiffer RM, Wheeler W et al.(2009) Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. Int J Cancer 25(12):2912-7.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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