Monoallelic germline RAD51C, RAD51D, and BRIP1 variants in hereditary cancer testing: Variant spectrum and clinical...

Defects in homologous recombination repair genes contribute to hereditary cancer susceptibility beyond BRCA1 and BRCA2, yet clinical interpretation of intermediate-penetrance genes remains challenging. We retrospectively evaluated unrelated carriers of pathogenic or likely pathogenic germline variants in RAD51C, RAD51D, and BRIP1 identified through hereditary cancer multigene panel testing in a real-world cohort of approximately 8000 individuals. Fifty-two carriers were included (RAD51C n = 14, RAD51D n = 15, BRIP1 n = 23). Ovarian cancer represented the predominant malignancy, followed by breast cancer, consistent with established gene-phenotype associations. Most detected variants were predicted loss-of-function alterations. Six previously unreported variants were identified, expanding the mutational spectrum of RAD51C and RAD51D. Recurrent variants were observed in unrelated individuals, including BRIP1 c.2992_2995del, which demonstrated higher frequency in regional population data compared with global datasets, suggesting possible population enrichment. Additional pathogenic variants in ATM and BRCA1 were identified in two individuals, highlighting the complexity of multigene testing. Although non-classical tumour types were occasionally observed, including colorectal cancer in BRIP1 carriers, causal associations remain uncertain. These findings emphasize the importance of population-aware variant interpretation and individualized genetic counseling aligned with contemporary ACMG and ESMO recommendations for moderate-penetrance hereditary cancer genes.