PO-076 Molecular analysis of BRCA-negative breast and/or ovarian cancer families by multigene panel testing

Introduction About 5%–10% of the hereditary breast and/or ovarian cancer (BC/BOC) is associated with an autosomal dominant genetic susceptibility due to highly penetrant mutations of the BRCA1/2 genes. In particular, BRCA1/2 gene mutations are found in 25%–30% of the BC families subjected to genetic testing. These numbers suggest the possible involvement of other genes in BC/BOC genetic predisposition and a fraction of these cases remains to be assigned to specific genetic factors. Here we report on the application of the NGS multigene panel to a group of BRCA1/2 mutation negative BC/BOC cases, in order to identify germline mutations that could further explain BC/BOC genetic susceptibility. Material and methods We selected a group of 27 BRCA1/2 negative BC and BOC families on the basis of a clear dominant inheritance pattern and/or a moderate/high BRCAPro score. We performed a genomic screening by a comprehensive multi-gene custom panel of 29 cancer-related genes, using Ion Torrent platform (Thermo Fisher Scientific). Results and discussions In three cases (11%) we found mutations described as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/) in ATM, MUTYH and PALB2 genes. In the series analysed, the most frequently altered genes were APC and ATM (15%) but were also identified mutations in MSH6 and TP53 (11%), MUTYH and RAD51B (7%), MRE11, EPCAM, BRIP1, CHEK2, PALB2, BARD1, STK11 and RAD50 (4%). In particular, we found six genomic variants of uncertain significance (VUS) in MSH6, ATM, BRIP1, RAD50 and APC genes; nine genomic variants of conflicting interpretations of pathogenicity in MUTYH, MRE11, TP53, APC, MSH6, CHEK2, EPCAM and ATM genes and eight genomic variants not reported in ClinVar in APC, RAD51B, STK11, TP53, ATM and BARD1 genes predicted deleterious by in silico analysis. Their biological significance and involvement in the development of the pathology is still unknown today. Only six patients were negative for the presence of mutations in the 29 genes analysed. Conclusion Preliminary results of this study suggest that NGS could offer a great contribution to identify the genetic component of susceptibility to BC/BOC and could potentially be used with implications for clinical management and counselling of patients and their families. Moreover, our results suggest that multigene testing approach may benefit appropriately selected patients, especially those with increased risk of BC/BOC development.