Medical Policy: 02.04.41
Original Effective Date: July 2012
Reviewed: February 2018
Revised: February 2018
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Some cases of cutaneous malignant melanoma (CMM) are familial. Potential genetic markers for this disease are being evaluated in affected individuals with a family history of disease and in unaffected individuals in a high-risk family.
A genetic predisposition to cutaneous malignant melanoma (CMM) 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)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 principal genes involved in CMM susceptibility have been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A), located on chromosome 9p21, encodes proteins that act as tumor suppressors. Variants in this gene can alter the tumor suppressor function. The second gene, cyclin-dependent kinase 4 (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 disease-associated variants 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 disease-associated variant. Variants are also infrequent in those with an early age of onset or those with multiple primary melanomas. However, the incidence of CDKN2A disease-associated variants increases with a positive family history; CDKN2A disease-associated variants 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. Variant detection rates in the CDKN2A gene are generally estimated as 20-25% in hereditary CMM but can vary between 2% and 50%, depending on the family history and population studied. Validated clinical risk prediction tools to assess the probability that an affected individual carries a germline CDKN2A variant are available.
Familial 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. Others have defined familial 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. No widely accepted guidelines for the management of families with hereditary risk of melanoma exist.
Other malignancies associated with familial CMM, specifically those associated with CDKN2A variants, 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.
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 variants, some family members with multiple atypical nevi who were noncarriers of the CDKN2A familial variant. Thus, the nevus phenotype cannot be used to distinguish carriers from noncarriers of CMM susceptibility in these families.
Some common allele(s) are associated with increased susceptibility to CMM but have low to moderate penetrance. One gene of moderate penetrance 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® (Myriad Genetics. Salt Lake City, UT) is commercially available genetic test of the CDKN2A gene. Melaris® testing assesses a person’s risk of developing hereditary melanoma by detecting inherited mutations in the p16 gene (also called CDKN2A or INK4A). The proposed benefits for this testing include: personalized patient care and increase clinical efficacy by targeting screening and surveillance specifically to individuals with p16 gene mutation; improve patient compliance with tailored screening recommendations and preventative measures; improve outcomes through earlier diagnosis and treatment of cancer; counsel patients and their family members on the underlying cause of the pattern of melanoma; and avoid unnecessary interventions for family members who do not test positive for the mutation known to be in the family.
MelanomaNext (Ambry Genetics) is genetic testing for hereditary melanoma and analyzes 8 genes (BAP1, BRCA2, CDK4, CDKN2A, MITF, PTEN, RB1 and TP53) that are linked to an increased lifetime risk of melanoma. All genes are evaluated by next generation sequencing (NGS) or Sanger sequencing. The proposed benefits to this genetic testing include the healthcare provider adjusting an individual’s cancer screening plan (such as age of initial screening, type and frequency) which may include a dermatology exam; healthcare provider may discuss possible cancer prevention options to reduce the risk of melanoma; and the healthcare provider may discuss the possibility of other personalized treatment options based on the genetic test result.
The purpose of genetic testing of individuals with cutaneous malignant melanoma (CMM) and family history of the disease is to identify variants in genes association with familial CMM to inform management decisions and potentially inform the decision to test asymptomatic family members for variants associated with familial CMM.
Clinical validity is related to interpretation of the results of genetic analysis for the individual patient. One issue common to genetic testing for any type of cancer susceptibility is determining the clinical significane of the individual variants. For example, variants in the CDKN2A gene can occur along its entire length, and some of these variants are benign. Interpretation will improve as more data accumulate on the clinical significance of individual variants in families with known hereditary pattern of melanoma. However, the penetrance of a given variant will also affect its clinical significance, particularly because the penetrance of CDKN2A variants may vary with ethnicity and geographic location. For example, exposure to sun and other environmental factors, as well as behavior and ethnicity, may contribute to penetrance.
Interpretation of a negative test is another issue. CDKN2A variants 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.
For example, in a 2011 meta-analysis of 145 genome-wide association studies, 8 independent genetic loci were identified as associated with statistically significant risk of cutaneous melanoma, including 6 with strong epidemiologic credibility (MCR1, TYR, TYRP1, SLC45A, ASIP/PIGU/MUH7B, CDKN2A/MTAP). Also, in a 2011 meta-analyses 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 also were associated with an increased risk of melanoma. In a 2012 review, Ward et. al. noted the genetics of melanoma are far from being understood, and “it is likely a large number of single nucleotide polymorphisms (SNPs), each with a small effect and low penetrance, in addition to the small number of large effect, high penetrance SNPs, are responsible for cutaneous malignant melanoma (CMM) risk.”
In 2010, Kanetsky et. al. conducted a study to describe associations between MC1R (melancortin 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. The study population included melanoma patients (n=960) and controls (n=396) who self-reported phenotypic characteristics and sun exposure information. Logistic regression was used to estimate associations between 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 (low risk odds ratio [OR], 1.7; 95% confidence interval [CI], 1.0 to 2.8; high risk OR = 2.2; 95% CI, 15. To 3.0). However, risk was noted to be stronger in or limited to people 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 indicated MC1R genotype provided information about melanoma risk in those individuals who would not be identified as high risk based on their phenotypes or exposure alone. However, how this information impacts patient care and clinical outcomes is unknown.
In 2012, Cust et. al. classified 565 patients with invasive CMM diagnosed between 18 and 39 years of age, 518 sibling controls, and 409 unrelated controls into MC1R categories defined by the presence of high risk or other alleles. Compared with sibling controls, 2 MC1R high risk alleles (R151C, R160W) were associated with increased odds of developing melanoma (R151C OR=1.7; 95% CI, 1.1 to 2.6; R160W OR=2.0; 95% CI, 1.2 to 3.2), but these associations were no longer statistically significant in analyses adjusted for pigmentation, nevus count, and sun exposure. Compared with unrelated controls, only the R151C high risk allele was associated with increased odds of developing melanoma in adjusted analysis. There was no association between other MC1R alleles (not considered high risk) and the odds of developing melanoma in unadjusted or adjusted analyses.
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. 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 the different factors, including the genetic heterogeneity of the Sicilian population. It is likely that 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 (e.g. latitude, sun exposure), could determine the occurrence of melanoma.
Studies have indicated that the clinical sensitivity of genetic testing associated with familial cutaneous malignant melanoma (CMM) is difficult to ascertain due to differences in gene penetrance, variant interpretation, study populations, sun exposure and preventative measures. The clinical validity of genetic variants associated with familial CMM is lacking.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Preferred evidence comes from randomized controlled trials (RCTs). No such trials were identified.
Although genetic testing for CDKN2A variants is recognized as an important research tool, its clinical use will depend on how results of genetic analysis can be used to improve patient management and health outcomes. Currently, management of patients considered 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. Presently, it is unclear how genetic testing for CDKN2A would alter these management recommendations.
If an affected individual tests positive for a CDKN2A variant, he or she may be at increased risk for a second primary melanoma compared with 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 variant. However, a positive result will establish a familial variant, thus permitting targeted testing in the rest of the family. Additionally, a positive variant in an affected family member increases the likelihood of its clinical significance if detected in another family member. As described earlier, a negative test is not interpretable.
Published data on genetic testing of the CDKN2A and CDK4 genes have focused on the underlying genetics of hereditary melanoma, identification of variants in families at high risk of melanoma, and risk of melanoma in those harboring these variants. Other studies have focused on the association between CDKN2A and pancreatic cancer.
Direct evidence of clinical utility of genetic testing in individuals with melanoma and a family history of disease is lacking. While genetic variants associated with increased risk for developing melanoma have been identified, changes in clinical management and improved health outcomes as a result of genetic testing for individuals with melanoma is uncertain.
The purpose of genetic testing of asymptomatic individuals in a family at high risk of developing cutaneous malignant melanoma (CMM) is to identify variants in genes associated with melanoma for increased surveillance to potentially detect disease at an earlier, more treatable stage.
For asymptomatic individuals in a family at high risk for developing melanoma, clinical validity is the diagnostic performance of the test (sensitivity, specificity, and negative predictive values) in risk assessment for predicting melanoma development in asymptomatic individuals.
In 2009, Yang et. al. conducted a study to identify modifier genes for cutaneous malignant melanoma (CMM) in CMM prone families with or without CDKN2A mutations. Investigators genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A+, 9 CDKN2A-) 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 variant positive families (BCL7A, IL9), while some were stronger in CDKN2A variant negative families (BCL2L1). The authors concluded that the analysis was limited by the small number of CMM cases particularly in analyses stratified by CDKN2A status. The stronger effects of most genes in CDKN2A positive families may be due to the smaller number of CDKN2A negative families examined in the study. The study should be viewed as an exploratory study and replication in larger samples is warranted. Also, they noted they could not adequately assess the interaction of genetic factors and host factors and sun exposure related variable. Because of small numbers, they used MC1R variants as surrogate for skin type, eye/hair color, and sun burn/tanning abilities. They included nevi as a covariate in all models with CMM as the outcome variable. Adjustments for MC1R and nevi did not change results significantly, suggesting that these SNPs might be risk factors of CMM independently from host factors and sun exposure. The study was also limited by the selection of genes and pathways included as the panel did not include all genes or SNPs that were found to be important in CMM by previous studies. Despite these limitations the authors considered these findings supportive of the hypothesis that common genetic variants in DNA repair, apoptosis and immune response pathways may modify the risk of CMM in CMM prone families with and without CDK2NA variants.
In 2013, Puntervoll et. al. described the phenotype of individuals with CDK4 variants in 17 melanoma families (209 individuals; 62 cases, 160 related controls, 41 unrelated controls). Incidence of atypical nevi was higher in those with CDK4 variants (70% in melanoma patients vs 75% in unaffected individuals) than in those without CDK4 variants (27%; p<0.001). The distribution of eye color or hair color did not differ statistically between CDK4 variant positive individuals (with or without melanoma) and variant negative family members. The authors concluded that it is not possible to distinguish CDK4 melanoma families from those with CDKN2A variants based on a phenotype. The clinical implication is that, although CDK4 mutation carriers are rarely seen, exon 2 of this gene should be examined in melanoma families seeking gene testing whenever tests are negative for CDKN2A.
Studies have indicated that clinical sensitivity of genetic testing for genes associated with familial cutaneous malignant melanoma (CMM) is difficult to ascertain due to differences in gene penetrance, variant interpretation, study populations, sun exposure, and preventative measures. For asymptomatic individuals in a family a high risk for developing melanoma, identification of genetic variants provides minimal value in risk assessment due to the multifactorial nature of disease development and progression.
If the asymptomatic individual is the first to be tested in the family (i.e. no affected relative has been previously tested to define a familial variant), it is very difficult to interpret the clinical significance of a variant, as described. The likelihood of clinical significance is increased if the identified variant is the same as that reported in other families, although the issue of penetrance is a confounding factor. If the asymptomatic individual has the same variant 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.
In 2008, Aspinwall et. al. found short term change in behavior among a small group of patients without melanoma who tested positive for the CDKN2A variant. In this prospective study of 59 members of a CDKN2A variant 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 disease associated variant 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 2011, a retrospective case control study, van der Rhee et. al. sought to determine whether a surveillance program of families with a Dutch founder variant in CDKN2A (the p16 Leiden variant) allowed for earlier identification of melanomas. Characteristics of 40 melanomas identified in 35 unscreened patients (before heredity was diagnosed) were compared with 226 melanomas identified in 92 relatives of those 35 unscreened melanoma patients who were found to have the CDKN2A variant and participated in a surveillance program over a 25 year period. Surveillance comprised 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 0.55 mm) than melanomas identified in 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 < 24 months) and melanoma tumor thickness at the 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.
In 2013, Aspinwall et. al. conducted a study to determine the short and long term impact of CDKN2A/p16 genetic counseling and test reporting on psychological distress, cancer worry, and perceived costs and benefits of testing. Prospective changes in anxiety, depression, and cancer worry following CDKN2A/p16 counseling and test reporting were evaluated at multiple assessments over 2 years among 60 adult members of melanoma prone families. Thirty-seven participants completed the 2 year follow-up. The study reported that anxiety and depression were low. For carriers and non-carriers, anxiety decreased significantly throughout the 2 year period, whereas depression and melanoma worry showed short-term decreases. In all groups, test related distress and uncertainty were low, regret was absent and positive experiences were high. All participants (>93% at each assessment) reported at least one perceived benefit of genetic testing, only 15.9% listed any negative aspect. Carriers reported increased knowledge about melanoma risk and prevention (78.3%) and increased prevention and screening behaviors for self and family (65.2%). Non-carriers reported increased knowledge (95.2%) and emotional benefits (71.4%). The authors concluded among U.S. participants familiar with their hereditary melanoma risk through prior epidemiological research participation, CDKN2A/p16 genetic testing provides multiple perceived benefits to both carriers and non-carriers without inducing distress in general or worry about melanoma.
In 2013, Aspinwall et. al. conducted a study evaluating the long-term impact of melanoma genetic test reporting and counseling on screening adherence. This study assessed adherence to recommendations for annual total body skin examinations (TBSEs) and monthly skin self-examinations (SSEs) among 37 members of Utah CDKN2A/p16 kindreds (10 unaffected carriers, 11 affected carriers, 16 unaffected carriers; response rate = 64.9% of eligible participants). Two years following test reporting, adherence to annual TBSE among unaffected carriers increased from 40% to 70%. However, unaffected non-carriers adherence decreased from 56% to 13%. Affected carriers reported TBSEs at both assessments 91% and 82% respectively. Monthly SSE frequency remained highly variable in all patient groups: at 2 years, 29.7% reported monthly SSEs, 27.0% reported more frequent self-examinations, and 43.2% reported under-screening. However, SSE quality improved: participants checked more body sites at 2 years than at baseline, especially feet, shoulders, legs and genitals. Perceived logistic barriers to TBSEs (e.g. expensive, inconvenient) and SSEs (hard to remember, time consuming) predicted lower adherence. The primary limitation to this study is the modest sample size and this limitation was compounded by the high level of variability in reported SSE frequency. The conclusions presented in this study await data from larger studies powered to analyze complex changes in SSE frequency in each patient group. An additional limitation is the high degree of prior research involvement of all patients in the present study, participants had not only received extensive prior counseling, but also demonstrated considerable commitment to melanoma research by participating in two prior studies over a period of several years. With respect to the possibility that participants were especially motivated, investigators obtained very high levels of participation in the initial test reporting phase of the study, along with the 2 year follow-up rate of 64.9%. It is unknown whether members of high risk families without prior research participation would respond similarly to melanoma genetic counseling and test reporting. The authors concluded unaffected carriers reported increased TBSE adherence and thoroughness of SSEs 2 years following melanoma genetic test reporting, suggesting clinical benefit in this modest sample. Unaffected non-carriers reportable gains in SSE thoroughness, but decreased TBSEs. Melanoma genetic counseling and test reporting may improve adherence among affected carrier members of CDKN2A/p16 families. Further investigations to distinguish the impact of receiving genetic test results from general genetic education and counseling is needed to determine how these different types of information effect adherence and motivation. Intervention efforts should also target logistic barriers to screening.
In 2013, van der Rhee et. al. reported on a retrospective case-control study of 21 families with the p16 Leiden founder variant. The purpose of the study was to investigate the yield of surveillance of first and second degree relatives of patients with melanoma (n=14 families) or with melanoma and pancreatic cancer (n=7 families). Overall, melanoma incidence rates were 9.9 per 1000 person-years (95% CI, 7.4 to 13.3) in first degree relatives and 2.1 per 1000 person-years (95% CI, 1.2 to 3.8) in second degree relatives. Compared with the general Dutch population, overall standardized morbidity ratios for melanoma were 101.0 (95% CI, 55.9 to 182.3) in first degree relatives (observed 45; expected 0.76) and 12.9% (95% CI, 7.2 and 23.4) in second degree relatives (observed 11; expected 0.53). Although the authors concluded that surveillance of second as well as first degree relatives from very high risk melanoma families were justified based on these findings, it is unclear whether these findings apply to families without or with other CDKN2A variants. Further, because increased sun protection and surveillance are recommended for any member of high-risk family, the clinical relevance of these findings is uncertain.
Direct evidence of the clinical utility of genetic testing in asymptomatic individuals in a family at high risk for developing cutaneous malignant melanoma (CMM) is lacking. While familial variants associated with increased risk for developing melanoma have been identified, changes in clinical management and improved health outcomes as a result of genetic testing for asymptomatic individuals is uncertain.
For individuals who have cutaneous malignant melanoma and a family history of this disease who receive genetic testing for genes associated with familial cutaneous malignant melanoma, the evidence includes genetic association studies between variants in certain genes and the risk of developing cutaneous melanoma. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given mutation, and residual risk with a benign variant. Currently, management of melanoma patients do not change based on genetic variants identified in genes associated with familial cutaneous malignant melanoma, therefore, clinical utility is lacking. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who are asymptomatic and in a family at high risk of developing cutaneous malignant melanoma who receive genetic testing for genes associated with familial cutaneous malignant melanoma, the evidence includes genetic association studies between variants in certain genes and the risk of developing cutaneous malignant melanoma. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given variant, and residual risk with a benign variant. Currently, management of patients considered at high risk for cutaneous malignant melanoma focuses on reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. It is unclear how genetic testing for variants associated with increased risk of cutaneous malignant melanoma would alter these management recommendations; therefore, clinical utility is lacking. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Melanoma Version 2.2018 current National Comprehensive Cancer Network (NCCN) clinical practice guidelines for melanoma include no specific recommendations regarding CDKN2A genetic testing for melanoma.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Melaris® and other CDKN2A tests are laboratory-developed tests (LDTs) and available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require any regulatory review of this test.
See also medical policy 02.04.53 Gene Expression Profiling of Melanomas
Genetic testing for genes associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.
The evidence to date is insufficient to permit conclusions concerning the effect of genetic testing for melanoma on health outcomes. Although research continues in this area, none of the articles identified demonstrate how the presence or absence of the gene mutation would impact clinical care, either for those with melanoma or for those at risk due to family history. Changes in patient management that result from finding a mutation in a patient at risk is unknown. In addition, not finding a mutation does not exclude the presence of familial cutaneous malignant melanoma. Therefore, genetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.
Commercially available tests include but are not limited to:
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