Medical Policy: 02.04.41 

Original Effective Date: July 2012 

Reviewed: February 2016 

Revised: April 2014 


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.


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) in the case of 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 CMM susceptibility have now been identified.  Cyclin-dependent kinase inhibitor 2A (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,  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 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. 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. Mutation 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.


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.


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.


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 noncarriers of the CDKN2A familial mutation. 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.


Commercially Available Test

Melaris® (Myriad Genetics. Salt Lake City, UT) is commercially available genetic test of the CDKN2A.



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.


Practice Guidelines and Position Statements

American Society of Clinical Oncology (ASCO)

In 2010 ASCO updated its policy statement on genetic and genomic testing for canced suspceptibility.  ASCO recommends that "genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials."


Melanoma Genetics Consortium

The Melanoma Genetics Consortium, compromising of familial melanoma researchers from North America, Europe and Australia, indicated that genetic testing for melanoma susceptibility should not be offered outside the research setting. There is difficulty in interpreting test results and there is potentially limited impact of the results on clinical management.


National Comprehensive Cancer Network (NCCN)

Melanoma Version 2.2016:

Current National Comprehensive Cancer Network (NCCN) clinical practice guidelines for melanoma include no specific recommendation for genetic testing for melanoma.


Regulatory Status

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.


Prior Approval:


Not applicable



Genetic molecular testing for mutations 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.  


Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 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 dyanamic mutation disorder/triplet repeat by Southern blot analysis)-Component within this panel CDKN2A (cyclin dependent kinase inhibitor 2A) (eg CDKN2A related cutaneous malignant melanoma familial atypical mole malignant melanoma syndrome), full gene sequence


Selected References:

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  • Agency for Healthcare Research and Quality (AHRQ) External Site Comparative Effectiveness Review Number 98, PCA3 Testing for the Diagnosis and Management of Prostate Cancer, April 2013.
  • ECRI. Product Brief. 4Kscore Test (OPKO Lab) for Predicting Risk of High Grade Prostate Cancer, June 2014.
  • < href="">Agency for Healthcare Research and Quality (AHRQ) External Site Evidence Report/Technology Assessment Number 209, Multigene Panels in Prostate Cancer Risk Assessment. 2012. External Site
  • ECRI External SiteEGAPP (Evaluation of Genomic Applications in Practice in Prevention) Working Group Recommendation, Does PCA3 Testing for the Diagnosis and Management of Prostate Cancer Improve Patient Health Outcomes.
  • National Comprehensive Cancer Network (NCCN)External Site External SiteProstate Cancer Early Detection Version 2.2015.
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  • OPKO Lab. 4Kscore Test.
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  • Porpiglia F, Russo F, Manfredi M, et al. The roles of multiparametric MRI, PCA3, and PHI: which is the best predictor of prostate cancer after a negative biopsy? Results of a prospective study. J Urol. Feb 8 2014. PMID 24518780
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  • Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol. Dec 20 2014;32(36):4066-4072. PMID 25385735
  • Ruffion A, Devonec M, Champetier D, et al. PCA3 and PCA3-based nomograms improve diagnostic accuracy in patients undergoing first prostate biopsy. Int J Mol Sci. 2013;14(9):17767-17780. PMID 23994838
  • Ruffion A, Perrin P, Devonec M, et al. Additional value of PCA3 density to predict initial prostate biopsy outcome. World J Urol. Feb 6 2014. PMID 24500192
  • Mackinnon AC, Yan BC, Joseph LJ, et al. Molecular biology underlying the clinical heterogeneity of prostate cancer: an update. Arch Pathol Lab Med. Jul 2009;133(7):1033-1040. PMID 19642730
  • Laxman B, Tomlins SA, Mehra R, et al. Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia. Oct 2006;8(10):885-888. PMID 17059688
  • Laxman B, Morris DS, Yu J, et al. A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res. Feb 1 2008;68(3):645-649. PMID 18245462
  • Rice KR, Chen Y, Ali A, et al. Evaluation of the ETS-related gene mRNA in urine for the detection of prostate cancer. Clin Cancer Res. Mar 1 2010;16(5):1572-1576. PMID 20160063
  • Leyten GH, Hessels D, Jannink SA, et al. Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. Eur Urol. Mar 2014;65(3):534-542. PMID 23201468
  • Yao Y, Wang H, Li B, et al. Evaluation of the TMPRSS2:ERG fusion for the detection of prostate cancer: a systematic review and meta-analysis. Tumour Biol. Oct 20 2013. PMID 24142545
  • Tomlins SA, Aubin SM, Siddiqui J, et al. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci Transl Med. Aug 3 2011;3(94):94ra72. PMID 21813756
  • Salami SS, Schmidt F, Laxman B, et al. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol Oncol. Jul 2013;31(5):566-571. PMID 21600800
  • Robert G, Jannink S, Smit F, et al. Rational basis for the combination of PCA3 and TMPRSS2:ERG gene fusion for prostate cancer diagnosis. Prostate. Jan 2013;73(2):113-120. PMID 22674214
  • Ma W, Diep K, Fritsche HA, et al. Diagnostic and prognostic scoring system for prostate cancer using urine and plasma biomarkers. Genet Test Mol Biomarkers. Mar 2014;18(3):156-163. PMID 24512523
  • Qu X, Randhawa G, Friedman C, et al. A three-marker FISH panel detects more genetic aberrations of AR, PTEN and TMPRSS2/ERG in castration-resistant or metastatic prostate cancers than in primary prostate tumors. PLoS One. 2013;8(9):e74671. PMID 24098661
  • Robinson K, Creed J, Reguly B, et al. Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay. Prostate Cancer Prostatic Dis. Jun 2010;13(2):126-131. PMID 20084081
  • Eilers T, Machtens S, Tezval H, et al. Prospective diagnostic efficiency of biopsy washing DNA GSTP1 island hypermethylation for detection of adenocarcinoma of the prostate. Prostate. May 15 2007;67(7):757-763. PMID 17373715
  • Ellinger J, Albers P, Perabo FG, et al. CpG island hypermethylation of cell-free circulating serum DNA in patients with testicular cancer. J Urol. Jul 2009;182(1):324-329. PMID 19447423
  • Henrique R, Ribeiro FR, Fonseca D, et al. High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients. Clin Cancer Res. Oct 15 2007;13(20):6122-6129. PMID 17947477
  • Ellinger J, Bastian PJ, Jurgan T, et al. CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer. Urology. Jan 2008;71(1):161-167. PMID 18242387
  • Sunami E, Shinozaki M, Higano CS, et al. Multimarker circulating DNA assay for assessing blood of prostate cancer patients. Clin Chem. Mar 2009;55(3):559-567. PMID 19131636
  • Van Neste L, Herman JG, Otto G, et al. The Epigenetic promise for prostate cancer diagnosis. Prostate. Dec 7 2011. PMID 22161815
  • Trock BJ, Brotzman MJ, Mangold LA, et al. Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies. BJU Int. Jul 2012;110(1):56-62. PMID 22077694
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  • Ge YZ, Xu LW, Jia RP, et al. The association between RASSF1A promoter methylation and prostate cancer: evidence from 19 published studies. Tumour Biol. Dec 19 2013. PMID 24353088
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  • Haldrup C, Mundbjerg K, Vestergaard EM, et al. DNA methylation signatures for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer. J Clin Oncol. Sep 10  2013;31(26):3250-3258. PMID 23918943
  • Wojno KJ, Costa FJ, Cornell RJ, et al. Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study. Am Health Drug Benefits. May 2014;7(3):129-134. PMID 24991397
  • Partin AW, Van Neste L, Klein EA, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol. Oct 2014;192(4):1081-1087. PMID 24747657
  • Little J, Wilson B, Carter R, et al. Multigene panels in prostate cancer risk assessment. Evid Rep Technol Assess (Full Rep). Jul 2012(209):1-166. PMID 24423032
  • Kader AK, Sun J, Reck BH, et al. Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial. Eur Urol. Dec 2012;62(6):953-961. PMID 22652152
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  • Ishak MB, Giri VN. A systematic review of replication studies of prostate cancer susceptibility genetic variants in high-risk men originally identified from genome-wide association studies. Cancer Epidemiol Biomarkers Prev. Aug 2011;20(8):1599-1610. PMID 21715604
  • UpToDate External SiteMeasurement of Prostate Specific Antigen. Stephen Freedland M.D., Topic last updated January 23, 2015.
  • National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection Version 2.2016.


Policy History:

  • February 2016 - Annual review, Policy revised
  • March 2015 - Annual review, Policy revised
  • April 2013 - Annual review, Policy revised
  • June 2013 - Annual review, Policy revised
  • April 2013 - Interim review, Policy revised
  • February 2013 - Interim review, Policy revised
  • July 2012 - Interim review, Policy revised

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.


*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.