Mutations in BRCA1 and BRCA2 genes explain about 22% of families meeting testing criteria for hereditary breast/ovary cancer (HBOC). Next-generation sequencing based multi-gene panels allow the analysis of a high number of genes simultaneously with a high sensitivity and are currently integrated into clinical practice.
A total of 177 women/families with clinical criteria for HBOC underwent genetic testing with a 26-gene commercial panel related to hereditary cancer. The analysis included 150 women with a personal diagnosis of BC/OC meeting national consensus for testing except 7 patients that did not comply these criteria, 6 healthy women at high-risk with ≥1 BC/OC affected first-degree relative and 21 patients with a previous BRCA1/2 negative result by other techniques.
A total of 11 BRCA1/2 mutations were identified three of which were previously undetected by other techniques. Mutations in other high or moderate BC/OC risk genes were found: one new mutation in RAD51D gene, two mutations in CHEK2 gene, one mutation in ATM gene, one mutation in PALB2 gene and two probably pathogenic variants in PALB2 and CHEK2 genes (according to predictors in silico). In addition, 8 variants of uncertain significance were detected. Subsequently, members of any of these 18 HBOC families started presymptomatic genetic diagnosis and prevention strategies.
In contrast to traditional sequential testing, the incorporation of multi-gene panels in our clinical practice has allowed us to obtain a more efficient genetic diagnosis on a greater number of families. Detecting actionable mutations in either previous BRCA1/2 negative or other HBOC associated families will optimize candidate identification for changes in medical management. The determination of the pathogenicity of frequent variants of uncertain significance in high or moderate penetrance genes remains the main challenge for cancer geneticists.
Clinical trial identification
Legal entity responsible for the study
Hospital Santa Creu i Sant Pau
All authors have declared no conflicts of interest.