Damaging missense variants in innate immunity genes are associated with earlier age of breast cancer onset in BRCA1 185delAG carriers

Background Penetrance of breast cancer (BC) among women who carry pathogenic variants (PVs) in BRCA1 is incomplete, and the age at BC diagnosis varies considerably, even among carriers of the same PV, suggesting the involvement of genetic and non-genetic risk modifying factors. Polygenic Risk Score (PRS) models based on common sequence variants account for less than 10% of the total risk variability among BRCA1 PV carriers, indicating that further genetic modifiers remain to be identified. Methods Here, for the first time, we applied whole-exome sequencing for this challenge, investigating a cohort of 321 Israeli women carrying the BRCA1 185delAG founder PV. Results In our cohort, we found that harbouring additional putatively damaging missense variants in genes involved in innate immunity was significantly associated with earlier BC onset. The HR for carrying a missense variant in genes annotated to the top-scoring immune-related gene set NATURAL_KILLER_CELL_ACTIVATION was 3.62 (95% CI 1.96 to 6.67; p=3.8×10 -5 ). Conclusion These findings highlight a potential role for innate immune pathways as modifiers of BRCA1 penetrance and support the development of more refined, personalised risk prediction models.