Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non‐CDKN2A/CDK4 melanoma families

Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10–40% of melanoma‐prone families. In our study we comprehensively characterized 488 melanoma cases from 451 non‐CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom‐designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1‐families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88–4.68, p