Prevalence of Germline Variants in Breast, Ovarian, and Prostate Cancer in Uruguay

This study aimed to characterize the spectrum of germline pathogenic and likely pathogenic variants in cancer susceptibility genes among Uruguayan patients with breast, ovarian, or prostate cancer (BC, OvC, PCa) who self-funded multigene panel testing. We analyzed 119 unrelated adults (93 bc, 12 OvC, 14 PCa) who underwent clinical germline testing using commercially available next-generation sequencing panels (comprising both a 26 gene hereditary breast/ovarian subset and a comprehensive 85/90 gene panel). Variant classification followed international guidelines. Detection rates were calculated with 95% exact binomial confidence intervals. OvC and PCa cases were analyzed separately due to small sample sizes (n < 15). PGVs were found in 16/119 patients (13.4%): 10.8% in BC (10/93), 25% in OvC (3/12), and 21.4% in PCa (3/14). BRCA1/2 variants accounted for 25% of positive cases, while 61.5% involved non-BRCA genes (ATM, RAD51C, MUTYH). No recurrent founder mutations were detected, although MUTYH c.452A>G was observed in multiple unrelated individuals. Variants of uncertain significance were identified in 57% of BC patients (53/93), mostly missense variants in DNA repair genes. The mean age at diagnosis among PGV carriers was 50 years (range 32-66). The germline mutational spectrum in Uruguayan cancer patients is diverse. Most PGVs were found in genes other than BRCA1/2, supporting the use of MGPT for cancer risk assessment. Genetic testing should be considered for all cancer patients in Uruguay, regardless of ancestry or tumor type. Further research is needed to better understand the role of less-characterized genes in BC, OvC, and PCa predisposition.