Non-BRCA1/BRCA2 High-Risk Familial Breast Cancers are Not Associated with a High Prevalence of BRCAness

Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. Using genome sequencing, we first noted for non-BRCA1/BRCA2 tumours, only a small proportion (3/23) demonstrated features of BRCAness, with high HRDetect scores and concomitant somatic BRCA1 mutation or promoter hypermethylation to explain their BRCAness. Second, a small proportion (4/23) showed no features of BRCAness but had mutationally active tumours. Third, the remaining tumours lacked features of BRCAness and were mutationally quiescent. Only few families could be explained by pathogenic germline variants in other genes or polygenic risk score.