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  • Test code: 01561
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Melanoma Panel

Test description

The Invitae Melanoma Panel analyzes up to 12 genes associated with a hereditary predisposition to melanoma. These genes were selected based on available evidence to provide Invitae’s most comprehensive test targeting hereditary melanoma.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

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Primary panel (9 genes)

BAP1 BRCA2 CDK4 CDKN2A MITF POT1 PTEN RB1 TP53

Add-on Preliminary-evidence Genes for Melanoma (3 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

BRCA1 MC1R TERT

  • BAP1 hereditary cancer predisposition syndrome
  • hereditary breast and ovarian cancer (HBOC) syndrome
  • hereditary melanoma-pancreatic cancer syndrome
  • PTEN hamartoma tumor syndrome (PHTS)
  • hereditary retinoblastoma
  • Li-Fraumeni syndrome

Melanoma is a cancer of pigment-producing cells (melanocytes) that typically begins in the skin (cutaneous) but can also develop in the eyes or internal organs. Because most melanoma cells continue to produce melanin, they are usually brown or black, but some can appear pink, tan, or even white. Cutaneous melanomas can develop anywhere on the skin, but they are more likely to start on the trunk in men and legs in women. The neck and face are other common sites.

Dysplastic nevi are atypical moles that are benign but may resemble melanoma. They are associated with an increased risk of progressing to malignant melanomas. The higher the number of these moles an individual has, the greater the risk. Those who have 10 or more moles have 12 times the risk of developing melanoma compared to the general population. Individuals in melanoma-prone families frequently have dysplastic nevi, which require close monitoring for any change in size, shape, or color—signs of malignant transformation.

Most cases of melanoma are isolated and sporadic. The number of individuals who have an inherited risk of melanoma is unknown, but it is thought to be low. An estimated 8% of affected individuals also have a first-degree relative with melanoma and an estimated 1%–2% of people with melanoma have two or more affected close relatives.

Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. For gene-associated cancer risks, see the table below.

GeneMelanoma riskReferences (PMIDs)
BAP1 13% 26096145
BRCA2 elevated 10433620, 22187320
CDK4 elevated 25431349
CDKN2A 28%–67% 12072543, 16234564
MITF elevated 22080950, 22012259
POT1 elevated 24686846, 24686849
PTEN up to 6% 22252256
RB1 elevated 22355046
TP53 elevated 20522432

Elevated: There is evidence of association, but the penetrance and risk are not well characterized.

Most of the genes on this panel have autosomal dominant inheritance. BRCA2 is also associated with autosomal recessive Fanconi anemia.

This panel may be considered for individuals with a personal and/or family history of melanoma (two or more affected first- or second-degree relatives). Additional features suggestive of a hereditary melanoma syndrome include a personal or family history of:

  • prostate, breast, ovarian, uterine, kidney, pancreatic, or mesothelioma
  • two or more primary melanomas or associated cancers in an individual
  • male breast cancer
  • breast or ovarian cancer and Ashkenazi Jewish ancestry
  • skin findings, such as multiple nevi

  1. Tan, MH, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 2012; 18(2):400-7. doi: 10.1158/1078-0432.CCR-11-2283. PMID: 22252256
  2. Breast, Cancer, Linkage, Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 1999; 91(15):1310-6. doi: 10.1093/jnci/91.15.1310. PMID: 10433620
  3. Bishop, DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J. Natl. Cancer Inst. 2002; 94(12):894-903. doi: 10.1093/jnci/94.12.894. PMID: 12072543
  4. Begg, CB, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J. Natl. Cancer Inst. 2005; 97(20):1507-15. doi: 10.1093/jnci/dji312. PMID: 16234564
  5. Ruijs, MW, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J. Med. Genet. 2010; 47(6):421-8. PMID: 20522432
  6. Moran, A, et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam. Cancer. 2012; 11(2):235-42. PMID: 22187320
  7. Kleinerman, RA, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J. Clin. Oncol. 2012; 30(9):950-7. PMID: 22355046
  8. Horn, S, et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013; 339(6122):959-61. PMID: 23348503
  9. Aoude, LG, et al. Genetics of familial melanoma: 20 years after CDKN2A. Pigment Cell Melanoma Res. 2015; 28(2):148-60. doi: 10.1111/pcmr.12333. PMID: 25431349
  10. Gibbs, DC, et al. Inherited genetic variants associated with occurrence of multiple primary melanoma. Cancer Epidemiol. Biomarkers Prev. 2015; 24(6):992-7. PMID: 25837821
  11. Rai, K, et al. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin. Genet. 2015. PMID: 26096145
  12. Shi, J, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat. Genet. 2014; 46(5):482-6. PMID: 24686846
  13. Robles-Espinoza, CD, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat. Genet. 2014; 46(5):478-81. PMID: 24686849
  14. American Society of Clinical Oncology, Cancer.net: Familial Malignant Melanoma, http://www.cancer.net/cancer-types/familial-malignant-melanoma, Accessed August 2018.
  15. American Cancer Society, cancer.org: What is melanoma skin cancer? http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-what-is-melanoma Accessed August 2018.
  16. Popova, T, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am. J. Hum. Genet. 2013; 92(6):974-80. PMID: 23684012
  17. Wadt, KA, et al. A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clin. Genet. 2015; 88(3):267-72. PMID: 25225168
  18. Carbone, M, et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 2012; 10:179. PMID: 22935333
  19. Friedenson, B. The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers. BMC Cancer. 2007; 7:152. PMID: 17683622
  20. Zuo, L, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat. Genet. 1996; 12(1):97-9. PMID: 8528263
  21. Puntervoll, HE, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J. Med. Genet. 2013; 50(4):264-70. PMID: 23384855
  22. Goldstein, AM, et al. CDKN2A mutations and melanoma risk in the Icelandic population. J. Med. Genet. 2008; 45(5):284-9. PMID: 18178632
  23. Soura, E, et al. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome. J. Am. Acad. Dermatol. 2016; 74(3):395-407; quiz 408-10. PMID: 26892650
  24. Harinck, F, et al. Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas. J. Med. Genet. 2012; 49(6):362-5. PMID: 22636603
  25. Nelson, AA, Tsao, H. Melanoma and genetics. Clin. Dermatol. 2009; 27(1):46-52. PMID: 19095153
  26. Petronzelli, F, et al. CDKN2A germline splicing mutation affecting both p16(ink4) and p14(arf) RNA processing in a melanoma/neurofibroma kindred. Genes Chromosomes Cancer. 2001; 31(4):398-401. PMID: 11433531
  27. Sargen, MR, et al. CDKN2A mutations with p14 loss predisposing to multiple nerve sheath tumours, melanoma, dysplastic naevi and internal malignancies: a case series and review of the literature. Br. J. Dermatol. 2016; 175(4):785-9. PMID: 26876133
  28. Bahuau, M, et al. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res. 1998; 58(11):2298-303. PMID: 9622062
  29. Randerson-Moor, JA, et al. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum. Mol. Genet. 2001; 10(1):55-62. PMID: 11136714
  30. Goldstein, AM, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006; 66(20):9818-28. doi: 10.1158/0008-5472.CAN-06-0494. PMID: 17047042
  31. Binni, F, et al. Novel and recurrent p14 mutations in Italian familial melanoma. Clin. Genet. 2010; 77(6):581-6. PMID: 20132244
  32. McWilliams, RR, et al. Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur. J. Hum. Genet. 2011; 19(4):472-8. PMID: 21150883
  33. Harland, M, et al. Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom. Hered Cancer Clin Pract. 2014; 12(1):20. PMID: 25780468
  34. Berwick, M, et al. The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study. Cancer Epidemiol. Biomarkers Prev. 2006; 15(8):1520-5. PMID: 16896043
  35. Goldstein, AM, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J. Med. Genet. 2007; 44(2):99-106. doi: 10.1136/jmg.2006.043802. PMID: 16905682
  36. Potrony, M, et al. Update in genetic susceptibility in melanoma. Ann Transl Med. 2015; 3(15):210. PMID: 26488006
  37. Aspinwall, LG, et al. CDKN2A/p16 genetic test reporting improves early detection intentions and practices in high-risk melanoma families. Cancer Epidemiol. Biomarkers Prev. 2008; 17(6):1510-9. PMID: 18559569
  38. Lindor, NM, et al. Concise handbook of familial cancer susceptibility syndromes - second edition. J. Natl. Cancer Inst. Monographs. 2008; :1-93. PMID: 18559331
  39. Vasen, HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int. J. Cancer. 2000; 87(6):809-11. doi: 10.1016/s0016-5085(00)84701-0. PMID: 10956390
  40. Potrony, M, et al. Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. JAMA Dermatol. 2016; 152(4):405-12. PMID: 26650189
  41. Soura, E, et al. Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling. J. Am. Acad. Dermatol. 2016; 74(3):411-20; quiz 421-2. PMID: 26892651
  42. Bertolotto, C, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011; 480(7375):94-8. doi: 10.1038/nature10539. PMID: 22012259
  43. Ghiorzo, P, et al. Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history. Pigment Cell Melanoma Res. 2013; 26(2):259-62. PMID: 23167872
  44. Yokoyama, S, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011; 480(7375):99-103. PMID: 22080950
  45. Wadt, KA, et al. Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition. PLoS ONE. 2015; 10(3):e0122662. PMID: 25803691
  46. Sturm, RA, et al. Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients. J. Invest. Dermatol. 2014; 134(1):141-149. PMID: 23774529
  47. Read, J, et al. Melanoma genetics. J. Med. Genet. 2016; 53(1):1-14. PMID: 26337759
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  50. Eckerle Mize D, Bishop M, Resse E, et al. Familial Atypical Multiple Mole Melanoma Syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2009. Available from http://www.ncbi.nlm.nih.gov/books/NBK7030/ Accessed August 2018.
  51. Barnhill RL. Gennery A. Spitzoid melanocytic neoplasms (Spitz nevus and atypical Spitz tumors). In: UpToDate, Tsao (Ed), UpToDate, Waltham, MA. Accessed August 2018.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
BAP1 NM_004656.3
BRCA1* NM_007294.3
BRCA2* NM_000059.3
CDK4 NM_000075.3
CDKN2A* NM_000077.4; NM_058195.3
MC1R NM_002386.3
MITF* NM_000248.3
POT1 NM_015450.2
PTEN* NM_000314.4
RB1 NM_000321.2
TERT NM_198253.2
TP53* NM_000546.5

BRCA1: Sequence analysis includes +/- 20 base pairs of adjacent intronic sequence.
BRCA2: Sequence analysis includes +/- 20 base pairs of adjacent intronic sequence.
CDKN2A: Analysis supports interpretation of the p14 and p16 proteins.
MITF: Analysis is limited to the NM_000248.3:c.952G>A p.Glu318Lys variant.
PTEN: Deletion/duplication analysis covers the promoter region.
TP53: Deletion/duplication analysis covers the promoter region.