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 <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non‐ CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.
What's new?
Germline mutations in CDKN2A are major contributors to familial melanoma. These mutations, however, are responsible for only 10 to 40 percent of genetic susceptibility in melanoma‐prone families. In this study, 30 established and candidate melanoma susceptibility genes were investigated for associations with the disease in patients from 451 non‐ CDKN2A/ CDK4 melanoma families. From the candidate gene panel, (likely) pathogenic variants in BAP1 and MITF were identified in several families, and potentially deleterious variants were identified in the shelterin complex genes ACD and TERF2IP. These genes appear to play a significant role in familial melanoma predisposition and are therefore promising candidates for incorporation into comprehensive genetic tests.