Integrated approaches for tailoring risk assessment in potential or confirmed BRCA1/2 variant carriers

Background Prompt and proper identification of germline BRCA1/2 pathogenic variants (PVs) is essential to inform clinical decisions in breast cancer/ovarian cancer (BC/OC) patients and their families. Aim To improve identification and risk assessment of germline BRCA1/2 PV carriers. Materials and Methods Study_1: The recent ClinGen ENIGMA BRCA1/2 classification criteria were systematically applied to all the BRCA1/2 variants of uncertain significance (VUS) identified in our laboratory. Study_2: Pathogenicity and associated penetrance of the Italian founder BRCA1:c.5017_5019del(p.His1673del) variant were assessed by combining data from 72 Italian carrier families and additional sources. Study_3: Clinical-pathological features of OC patients associated with germline BRCA1/2 PVs were identified through a systematic literature review with meta-analysis and analyzed using logistic regression models and machine learning approaches in a series of 1009 OC patients to develop a risk score. Results Study_1: 135 out of 166 (81.3%) VUS detected in 231 index cases were re-classified: 128 (94.8%) as Benign/Likely Benign and 7 (5.2%) as Pathogenic/Likely Pathogenic. Study_2: BRCA1:c.5017_5019del(p.His1673del) variant carriers displayed significantly increased risk for OC (HR = 33.0, 95%) and uterine cancer (HR = 8.0), but not for BC (HR = 0.7). The variant was classified as Pathogenic for different types of evidence. Study_3: The systematic literature review with meta-analysis and the analysis of our OC cohort showed that histotype, family history of BC/OC, previous BC and age at diagnosis are independently and significantly associated with BRCA1/2 status. ORs derived from multivariable logistic regression calibrated according to machine learning analyses results were used to assign weights from 1 to 3 to each feature, developing a score ranging from 0 to 10 associated with increasing risk of BRCA1/2 PVs (score 0 =0.6%; score ≥7 =88%). Conclusions These results are relevant for a significant number of patients and families and could make their clinical management more precise and effective.