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The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted ( BRCA1/2 ) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at  BRCA2  (47/98),  BRCA1  (24/98),  PALB2  (8/51),  ATM  (7/51),  CHEK2  (6/51)  MSH6 , (2/51),  RAD51C  (2/51) and  TP53  (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for  BRCA1  and  MSH6  pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for  BRCA2  and  BRCA1  pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures ( p  = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from  BRCA1  and  BRCA2 , and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for  BRCA1/2  between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective