Association of type and location of germline BRCA1/2 PVs/LPVs with phenotype and prognosis in young breast cancer patients

A multinational retrospective cohort study by the BRCA BCY Collaboration investigated the association of type and location of germline BRCA1/2 pathogenic or likely pathogenic variants (PVs/LPVs) with phenotype and prognosis of breast cancer patients diagnose at the age of ≤ 40 years. Out of patients from 109 centers, 3294 were eligible for the analysis (2080 BRCA1 and 1214 BRCA2). The distribution of PV/LPV types showed no meaningful associations with baseline clinicopathologic features. BRCA1 protein truncating variant were associated with with worse OS compared to non-truncating variants (HR 2.00; 95% CI 1.17-3.41). A similar, but non-significant, trend was seen for BRCA2. Missense variants were linked to better OS for both BRCA1 (HR 0.48; 95% CI 0.28-0,84) and BRCA2 (0.17; 0.03-0.96) mutation carriers. Regarding variant location, BRCA1 PVs/LPVs outside exons 2, 10, and 19 were associated with improved OS. In BRCA2, PVs/LPVs located in exons 15-26 were linked to worse DFS compared to those in exon 10, without significant differences in OS (graphical abstract).