Comprehensive analysis of germline pathogenic variants across melanoma

Abstract Although a heritable component is implicated in ~10% of melanomas, the prevalence and functional relevance of germline pathogenic variants (gPVs) in unselected patients remains unknown. We evaluated 701 patients with melanoma who underwent tumor-normal MSK-IMPACT sequencing (2015–2023) and germline analysis of ≥76 cancer predisposition genes. Biallelic inactivation was assessed via loss of heterozygosity (LOH) and somatic second hits. Germline PVs were identified in 99 patients (14%), involving 33 genes. No significant differences were observed between patients with and without gPVs in clinicopathologic features, MAPK driver alterations, tumor mutational burden, or immunotherapy survival outcomes. Of 63 gPVs evaluable for zygosity, 20 (32%) exhibited biallelic inactivation, including 10 in high- or moderate-penetrance genes. In this unselected melanoma cohort, gPVs were common but often lack somatic inactivation. These findings support expanded germline testing in melanoma for cancer prevention, though many gPVs may not contribute to melanoma carcinogenesis via the classical “two-hit” framework.