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A.2.04.44
Cutaneous melanoma is the third most common type of skin cancer, but the most lethal. Some cases of cutaneous malignant melanoma are familial. Potential genetic markers for this disease are being evaluated in affected individuals with a family history of the disease and in unaffected individuals in a high-risk family.
Genetics of Cutaneous Malignant Melanoma
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 have been 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. Although some of the familial risk may be related to shared environmental factors, three (3) principal genes involved in cutaneous malignant melanoma 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 six (6) families worldwide. A third gene, not fully characterized, maps to chromosome 1p22.
Some common allele(s) are associated with increased susceptibility to cutaneous malignant melanoma 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 cutaneous malignant melanoma. This gene is associated with fair complexion, freckles and red hair; all risk factors for cutaneous malignant melanoma. Variants in MC1R also modify the cutaneous malignant melanoma risk in families with CDKN2A variants.
A 2012 review of the literature on germline melanoma susceptibility concluded that in addition to the two rare, high-penetrance variants (CDKN2A and CDK4), there are potentially many single nucleotide polymorphisms which have small effects and low penetrance.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Melaris® (Myriad Genetics) and other CDKN2A tests are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Genetic testing for genes associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational (See Policy Guidelines).
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA
Previous | Updated | Definition |
Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
Variant | Change in the DNA sequence | |
Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification | Definition |
Pathogenic | Disease-causing change in the DNA sequence |
Likely pathogenic | Likely disease-causing change in the DNA sequence |
Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
Likely benign | Likely benign change in the DNA sequence |
Benign | Benign change in the DNA sequence |
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Hereditary Cancer Syndromes and Screening Recommendations
Genetic susceptibility for melanoma can be a component in other hereditary cancer syndromes and therefore risk assessment and screening guidelines related to other cancers may be relevant to consider. See the Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2) , Genetic Testing for PTEN Hamartoma Tumor Syndrome , and Genetic Testing for Li-Fraumeni Syndrome medical policies.
NCCN v3.2024 guidelines for genetic/familial high-risk assessment in breast, ovarian, and pancreatic cancer recommend comprehensive skin examination by a dermatologist supplemented with biannual total body photography and dermoscopy for CDKN2A variant carriers. The publication referenced in the guidelines to support the recommendation is a review article that does not provide evidence that biannual total body photography and dermoscopy improves outcomes.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
5/18/2006: Approved by Medical Policy Advisory Committee (MPAC).
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.
11/28/2012: Policy reviewed; no changes to policy statement. Added CPT code 81404 to the Code Reference section.
12/02/2014: Policy reviewed; description updated. Policy statement unchanged.
12/31/2014: Code Reference section updated to revise the description of the following CPT code: 81404.
07/30/2015: Code Reference section updated for ICD-10.
02/12/2016: Policy description updated regarding laboratory-developed tests. Policy statement unchanged. Policy guidelines updated regarding genetic counseling and to define investigative.
06/06/2016: Policy number A.2.04.44 added.
03/27/2017: Policy description updated. Policy statement updated to change "mutations" to "genes." Policy guidelines updated regarding standard terminology for variant classification.
06/27/2017: Code Reference section updated to revise code description for CPT code 81404, effective 07/01/2017.
12/22/2017: Code Reference section updated to revise description for CPT code 81404 effective 01/01/2018.
01/16/2018: Updated policy statement to specify that DecisionDX-Melanoma™ is considered investigational.
04/03/2018: Policy description updated. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.
04/04/2019: Policy description updated regarding management of melanoma. Policy statement unchanged.
09/04/2019: Policy statement updated to remove DecisionDX-Melanoma™.
04/15/2020: Policy reviewed; no changes.
05/25/2021: Policy reviewed; no changes.
05/11/2022: Policy description updated. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.
04/14/2023: Policy title changed from "Genetic Testing for Familial Cutaneous Malignant Melanoma" to "Germline Genetic Testing for Familial Cutaneous Malignant Melanoma (CDKN2A, CDK4)." Policy description updated. Policy statement unchanged.
04/18/2024: Policy reviewed. Policy section updated to refer to the Policy Guidelines. Policy Guidelines updated regarding hereditary cancer syndromes and screening recommendations.
04/17/2025: Policy reviewed; no changes.
Blue Cross Blue Shield Association policy # 2.04.44
This may not be a comprehensive list of procedure codes applicable to this policy.
Code Number | Description |
CPT-4 | |
81404 | Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) |
84999 | Unlisted chemistry procedure |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
