Familial Melanoma Genes Associated With Expanded Spectrum of Malignancies

Key Takeaways

• Pathogenic variants in familial melanoma genes were identified in approximately 0.5% to 0.9% of nearly 700,000 genomically screened individuals from the UK and US.

• Individuals with multiple cutaneous melanomas or melanoma diagnosed before age 40 exceeded the commonly used 2.5% threshold for germline testing.

• The authors said cancer risks associated with several familial melanoma genes may extend beyond traditionally recognized malignancies.

A new study published in JAMA Dermatology suggests pathogenic variants (PVs) in familial melanoma susceptibility genes are present in up to 0.9% of the general population.

Investigators for the large genome-first study analyzed genomic and cancer registry data from 696,665 individuals enrolled in the UK Biobank (UKBB) and Geisinger MyCode (GMC) cohorts. The study aimed to estimate the prevalence of PVs in eight clinically actionable familial melanoma genes—ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, and the TERT promoter—without the ascertainment bias that can arise when only patients with personal or family cancer histories are evaluated.

Familial Melanoma Gene Variants Found in Up to 0.9% of Population Cohorts

The combined prevalence of pathogenic variants ranged from 0.5% in GMC to 0.9% in UKBB across the cohorts. Pathogenic variant prevalence was greater than the 2.5% threshold. The analysis confirmed previously reported associations between CDKN2A variants and cutaneous melanoma, pancreatic cancer, head and neck cancers, and brain tumors. Established links were also replicated for MITF E318K (melanoma and kidney cancer), and for POT1 (melanoma, hematologic malignancies, and thyroid cancer).

The authors reported several potentially novel (or previously inconsistently reported) associations such as links between BAP1 and prostate cancer; CDKN2A and biliary tract, breast, nonmelanoma skin, and small intestine cancers; MITF E318K and cervical, nonmelanoma skin, and nasal cavity cancers; and POT1 and multiple myeloma.

Individuals carrying CDKN2A variants or MITF E318K developed cutaneous melanoma at younger ages vs. noncarriers. Age-at-onset trends in the age of onset for internal malignancies were not as consistent.

“In this cohort study, the prevalence of pathogenic variants in familial melanoma genes and their associated cancer risks were estimated, findings that may inform and revise germline testing recommendations and cancer risk counseling,” the authors wrote. “These data also suggest that the spectrum of cancer risk for several genes may be broader than previously recognized.”

Source

Goldstein A, et al. JAMA Dermatol. Published Online: May 27, 2026 Doi: 10.1001/jamadermatol.2026.1305