Carlo MI, Ravichandran V, Srinavasan P, et al. - In this study with 586 patients with urothelial cancer (UC), researchers assessed the prevalence of pathogenic/likely pathogenic (P/LP) germline variants as well as explored associated clinical factors. Prospective, matched tumor-normal DNA sequencing was performed on the participants. Experts examined 77 genes related to cancer predisposition; they compared allele frequencies with publicly accessible database. In 80 (14%) patients, P/LP germline variants were detected. In high- or moderate-penetrance genes, the P/LP variants that were most common were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). A significant link of BRCA2 and MSH2 with an increased risk for UC was revealed. Findings highlighted a frequent presence of clinically significant P/LP germline variants in DNA-damage repair (DDR) genes among patients with advanced UC. For guiding cancer screening for patients as well as their families, and for predicting response to targeted or immunotherapies, the significance of the presence of DDR germline variants was evident. Family history–based criteria to recognize patients with hereditary UC susceptibility were identified as insensitive. Considering broader germline testing in UC, especially in those of young ages, was recommended.