Exome sequencing in BRCA1-2 candidate familias: the contribution of other cancer susceptibility genes.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (WES) we analyzed a series of 200 individuals selected for genetic testing in genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large deletions/duplications. Focusing on genes, data analysis identified 11 cases with pathogenic variants (4 in and 7 in ) and 12 with uncertain variants (7 in and 5 in ). Only one case was found with a large deletion. Whole exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (, , , , , , and ) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (, , , , , , , , and ). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate non-canonical genes.