Germline Mutational Spectrum of Brazilian Hboc Patients Tested with Hereditary Cancer Multigene Panels.

e13113 Background: Hereditary breast and ovarian cancer syndrome (HBOC) is a condition with significant phenotypic heterogeneity caused by mutations in BRCA1 and BRCA2. In addition, several other genes have been implicated in an increased risk of breast (BC) and ovarian cancer (OC). In the past years, multigene panels performed through next generation sequencing (NGS) were consolidated as a cost-effective method to access the germline mutational status of patients with HBOC-like phenotypes. We aimed to evaluate the mutational spectrum of patients fulfilling HBOC clinical criteria (according to the NCCN guidelines). Methods: NGS (including deletion/duplication analyses) were performed at a commercial laboratory in the USA using Illumina technology (minimum coverage 50x depth). For all 89 patients included in this study, at least seven genes were analysed (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11 and TP53). In a few patients, expanded panels (up to 48 genes) were used. Results: Most patients had BC (68%, mean age at diagnosis 44 years) or OC (3%, mean age at diagnosis 54 years), and 22 patients had only a family history of the disease. Overall, thirteen pathogenic variants were identified in four genes (2 in ATM, 5 in BRCA1, 4 in BRCA2 and 2 in MUTYH) and 40 variants of uncertain significance (VUS) were detected in 19 genes (APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, MEN1, MLH1, MSH2, MUTYH, NF1, PALLD, PMS2, PTCH1, RAD50, RAD51 and RET). Excluding patients negative for pathogenic mutations or VUS in BRCA1 or BRCA2 genes, multigene panel identified 29 VUS and 3 pathogenic mutations among 15 genes. Conclusions: These results shows that multigene panels contribute in the diagnosis of hereditary cancer predisposition, allowing the identification of patients who can benefit of surveillance strategies, and genetic counseling for additional at-risk relatives. Nevertheless, is important that a significant proportion of HBOC families remain without a molecular diagnosis and another significant number of patients are diagnosed with novel and/or variants of uncertain significance, mainly in in moderate/low penetrance genes, for which there are no management guidelines available.