Background: Hereditary RCCs account for 3-5% of all RCC cases. The prevalence and significance of germline PVs of RCC have not been fully characterized. Methods: We evaluated the frequency of pathogenic and likely pathogenic variants, referred to as PVs, in 1829 high-risk RCC pts who underwent targeted clinical germline testing (1-134 genes) at a commercial laboratory. PVs, including single nucleotide variants/indels/ copy number variants, were confirmed using orthogonal technology in accordance with Invitae’s standard operating practices. Actionable genes were defined as established cancer-predisposition genes that confer a higher risk for any cancer phenotype and for which enhanced screening and family genetic testing are recommended by the National Comprehensive Cancer Network. We focused our analysis on genes tested in more than 100 pts (n=93). Results: Among 1892 pts, 54.9% were male, and 68.9% were Caucasians, with median age 50 (range:1-87) years at RCC diagnosis. 11.8% (n=215) of pts had at least 2 primary RCCs, and 30.7% (n= 561) had a personal history of another cancer. The cumulative frequency of pts with PVs was 17.7%. PVs in known RCC susceptibility genes such as FH, FLCN, and SDHB were detected in 1.8% (29/1622), 1.22% (120/1634) and 0.64% (11/1727) of pts respectively. PVs in other cancer-associated genes were most frequently reported in CHEK2 (loss-of-function variants, 30/1276, 2.4%), MUTYH (19/1124, 1.7%), and BRCA2 (17/1276, 1.33%). PVs in DNA-damage repair genes (DRG) accounted for 71.8% of PVs and, overall, were detected in 12.7% of pts. Among the DRG, PVs in the homologous recombination pathway (ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RECQL4, WRN) were the most prevalent (7.8%) whereas the mismatch repair pathway (MLH1, MSH2, MSH6, PMS2) was altered in only 0.7% of pts. Of the examined cohort, 9.7% of pts had ≥1 actionable PV. In non-Caucasians, BRCA2 PVs were the most common (6/273, 2.20%). Conclusions: PVs were identified in 17.7% of RCC subjects, most of which (71.8%) were in DRG, with »10% of pts having actionable variants. Our work is concordant with known RCC susceptibility genes and potentially highlights novel risk genes that should be validated in future studies.