Results: BRCAPANCPRO yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUC = 0.84, 95% CI: 0.78, 0.87) and was reasonably well-calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.82 ). We then validated this model on three datasets each reflecting the target populations for these models, including patients referred to a high-risk genetics clinic, patients with multiple family members with pancreatic cancer who underwent genetic testing for BRCA1/2, as well as a prospective registry of pancreatic cancer families. Methods: We expanded the existing framework for PANCPRO and BRCAPRO to model underlying risk of pancreatic, breast, and ovarian cancer. Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO), and the risk of developing pancreatic cancer (PANCPRO). P>Introduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. This study helps address the gap in our understanding of BRCA -associated cancer in Latin America. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. The area under the ROC curve for BRCAPRO was 0.76. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs 160 BRCA1 (31% CNVs) 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. BRCA PV probability was calculated using BRCAPRO. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel ( HISPANEL ) on MassARRAY semiconductor sequencing and copy number variant (CNV) detection. This study aims to address this disparity. The prevalence and contribution of BRCA1 / 2 ( BRCA ) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood.
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