The germline DNA repair gene landscape in BRCA1 and BRCA2 implicated hereditary breast cancer families

As gene-panels expand to include candidate breast cancer predisposing genes (CPGs) involved in diverse DNA repair pathways, we investigated an index breast cancer (BC) case from 56 BRCA1 or BRCA2 implicated high-risk hereditary BC families for rare germline variants predicted to be damaging and clinically relevant in 276 DNA repair genes (DRGs). Using whole exome sequencing analyses, we identified a total of 287 variants in 55% of DRGs, of which 24 loss-of-function and 36 other predicted damaging variants were identified in 72% and 76% of BRCA1 and BRCA2 implicated cases, respectively. We also identified 60 variants of clinical interest in various known CPGs, including those involved in risk to other cancers, in 72% of BRCA1 and 60% of BRCA2 cases. The number of variants predicted to be deleterious in diverse DRGs raises questions about the interpretability of findings as panel testing expands beyond clinically established breast CPGs.