Germline Variants in Bladder and Upper Tract Urothelial Cancers: Prevalence and Clinical Context in a Large Testing Registry.

The prevalence and clinical history of germline variants in bladder cancer and upper tract urothelial cancer (UTUC) remains incompletely defined, particularly regarding mismatch repair (MMR) and homologous recombination repair (HRR) variants. This study aims to evaluate the prevalence of germline variants in patients with bladder cancer and/or UTUC referred for germline testing, and to report the personal and family cancer histories of patients with MMR (Lynch syndrome) and HRR variants. We retrospectively analyzed 3561 urothelial cancer patients (3130 with bladder cancer only, 370 with UTUC, and 61 with both) who underwent germline testing between 1996 and 2025 at Myriad Genetics. We describe the prevalence of pathogenic/likely pathogenic germline variants in patients with UTUC and bladder cancer, and characterize the personal and family cancer histories of patients with MMR (MSH2, MSH6, MLH1, and PMS2) and HRR (BRCA1 and BRCA2, among others) variants, comparing with an institutional cohort of MMR carriers (n = 35; 2012-2025). We also assess the proportion of MMR variant carriers who would be referred for testing under existing guidelines.Key findings and limitationsIn this cohort, 702 (20%) patients had pathogenic/likely pathogenic germline variants, including 328 patients with MMR and 298 patients with HRR variants. MMR variants were more common in UTUC, with 27% (n = 101) harboring an MSH2 variant compared with 7.6% (n = 109) of bladder cancer patients (p < 0.001). However, conversely, 58% (n = 109) of patients with an MSH2 variant had bladder-only disease. Prior nonurothelial cancers occurred in 54-63% of MMR and 35-41% of HRR carriers. Lynch syndrome is common in patients with UTUC; yet, many carriers present with bladder cancer alone. Personal and family cancer histories frequently precede urothelial cancer, underscoring the need for routine germline testing in UTUC and consideration of broader testing across urothelial cancer. Inherited genetic variants, especially those associated with Lynch syndrome, are common in patients with ureter and renal pelvis urothelial cancer. However, many patients with these variants have urothelial cancer of the bladder only. Broader genetic testing, particularly in those with a suggestive personal or family cancer history, may help identify patients at risk who might otherwise be missed.