153P Descriptive analysis of the location of point mutations in BRCA and the risk of breast or ovarian cancer diagnosis

Within BRCA carriers, there are data suggesting that not all alterations confer the same risk of breast or ovarian cancer. In addition, the localization of the mutation as a biomarker of response to targeted therapies such as iPARP is in the process of being validated. The distribution of mutations according to the functional domain in which they are located may be a good method for establish their role in cancer risk. We included all carriers from the registry of the Hereditary Cancer Unit. Functional domains (dom) of BRCA1 were defined as: Really Interesting New Gene (RING) from aa 8-96; DNA-binding dom (DBD) from aa 452-1092; and BRCA1 C terminal (BRCT) from aa 1650-1863 Functional doms of BRCA2 were defined as: PALB2-BD dom from aa 21-39, RAD51-binding dom (RAD51-BD) from aa 900-2000, and DBD from aa 2459-3190. 284 carriers were located. 66% women, 55% BRCA1 mutation carriers (mc). Of these, 63% healthy carriers (hc), half of whom were women. Among the BRCA1 muts, 55% of breast cancer (bc) were associated with BRCT muts compared with 5.5% in DBD. In the BRCT dom, the mean age at diagnosis (dx) of bc was 44 years, with 35% of luminal tumors. Among hc, only 33% were older than the mean age at dx. Among the BRCA2 muts, 61% of the cases with bc were associated with the RAD51-BD dom compared to 10% in the DBD dom. In the RAD51-BD dom, the mean age at dx of bc was 51 years, with 11% of cases being Her-2 positive and 29% triple negative. Among hc, only 40% were older than the median age at dx. As for ovarian cancer, a more heterogeneous pattern was observed, although again, the doms with the most cases were BRCT and RAD51-BD.Table: 153PBRCA 1BRCA 2TOTALRINGDBDBRCTOthersTotalPALB2-BDRAD51DBDOthersTotalHealthy carrier321413810325551981184Breast12201336117372864Ovarian12781806241230Pancreas00101010234Other tumors*01001060178Total5 (3.1%)26 (16.4%)69 (43.4%)59 (37.1%)1593 (2.3%)85 (64.9%)10 (7.6%)33 (25.2%)131290Mean age at diagnosis53634443.946515143494947*Other tumors: cholangiocarcinoma, medulloblastoma, urotelial, astrocitoma, cervical and melanoma, all with 1 case reported. Open table in a new tab *Other tumors: cholangiocarcinoma, medulloblastoma, urotelial, astrocitoma, cervical and melanoma, all with 1 case reported. The characterization of the mut population can provide data for the personalization of follow-up. In our population, the age of hc is shown as a bias for the definition of risk, so more follow-up and multicenter studies are needed to validate the results.