HEREDITARY MELANOMA

Hereditary Melanoma & Skin Cancer — CDKN2A mutations confer 60-90% lifetime melanoma risk, MC1R variants increase risk regardless of apparent skin type, and BAP1 predisposes to uveal melanoma and mesothelioma.

Whole genome sequencing evaluates all melanoma and skin cancer predisposition genes — CDKN2A, CDK4, MC1R, BAP1, POT1, TERT, MITF — providing comprehensive hereditary skin cancer risk assessment.

CDKN2A
CDK4
MC1R
BAP1
POT1
MITF

About this condition

Melanoma & Skin Cancer — Hereditary

Approximately 5-10% of melanoma is familial. CDKN2A/p16 (chromosome 9p21.3) is the highest-penetrance melanoma gene — pathogenic variants confer 60-90% lifetime melanoma risk (population and UV-exposure dependent). CDKN2A carriers also have 13-22x increased pancreatic cancer risk. CDK4 is a rarer high-penetrance melanoma gene. MC1R (melanocortin-1 receptor) red hair/fair skin variants (R151C, R160W, D294H) confer 2-4x melanoma risk each, with compound heterozygotes at higher risk.

BAP1 tumor predisposition syndrome causes uveal (ocular) melanoma, mesothelioma, and cutaneous melanocytic BAP1-mutated atypical intradermal tumors (MBAITs). POT1, TERT promoter, and MITF E318K are additional melanoma susceptibility genes identified through family studies.

Clinical implications: CDKN2A carriers require total-body skin examinations every 3-6 months and annual dermoscopy/photography. MC1R genotyping can identify individuals at elevated risk who don't have classic red-hair phenotype (R151C carriers can have brown hair). Sun protection counseling guided by MC1R genotype is an emerging precision prevention strategy.

MC1R variants increase melanoma risk 2-4x even in people who DON'T have red hair. Many MC1R carriers have brown hair and tan skin but carry elevated genetic melanoma risk invisible to clinical assessment.

Gene locus: CDKN2A (9p21.3), CDK4 (12q14.1), MC1R (16q24.3), BAP1 (3p21.1), POT1 (7q31.33), MITF (3p13)

Melanoma risk assessment based on skin color alone misses MC1R carriers without typical phenotype. Genetic testing provides objective risk assessment independent of appearance.

CDKN2A carriers need dermatologic surveillance every 3-6 months — plus pancreatic cancer screening

CDKN2A confers 60-90% melanoma risk AND 13-22x pancreatic cancer risk. Identification triggers both intensive dermatologic surveillance and pancreatic cancer screening (MRI/EUS). Without genetic testing, the pancreatic cancer risk component is never addressed.

MC1R genotyping identifies hidden melanoma risk — brown-haired carriers need enhanced sun protection

MC1R R151C carriers can have brown hair, hazel eyes, and some tanning ability — but still carry 2-4x melanoma risk. Clinical assessment alone would not identify these individuals as high-risk. WGS reveals MC1R genotype, enabling personalized sun protection counseling based on genetic rather than phenotypic risk.

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