Approximately 5% of renal cell carcinoma (RCC) is hereditary. Early age of onset ≤ 46 years in RCC patients has been suggested as a criterion for referral to genetic counseling based on epidemiological data. We sought to determine the prevalence of pathogenic germline variants in cancer associated genes in patients with early onset RCC seen at our institution and identify clinical and pathologic factors associated with the presence of germline mutations.

Overall, 233 patients with RCC diagnosed age ≤ 46 years agreed to germline sequencing with a targeted panel of >76 cancer-associated genes either through an institutional protocol of matched tumor-germline sequencing (n=165) or after a visit to clinical genetics clinic (n=68). Mutation prevalence and spectrum were determined. Clinicopathologic characteristics were assessed by mutation status. All statistical computations were performed using STATA version 12.1.

Mean age was 38 years (range 21-46), 39 (17%) patients had RCC family history, 34 (15%) had RCC-syndromic features, 122 (52.4%) had clear cell RCC (ccRCC). Germline mutations were identified in 43 (19%) patients. 21 (9%) had mutations in RCC-associated genes (12 FH, 4 VHL, 2 SDHB, 1 each BAP1, TSC1, and FLCN).11 (5%) had mutations in moderate/high penetrance non-RCC genes (2 in BRCA1, ATM, CHEK2, TP53, 1 in PALB2 and RET). For patients with RCC-associated mutations, 11 (52%) had syndromic features, 6 (29%) had RCC family history; 9 (43%) had neither. For RCC-associated mutations, all ccRCC (4 VHL and 1 BAP1) and only 7 (43.8%) non-ccRCC patients (5/12 FH, 1/2 SDHB , 1/1 TSC1, 0/1 FLCN) had syndromic features/family history. 7/9 (77.8%) patients with non-RCC genes met standard criteria for testing for those genes.

In our cohort of early onset patients identified to have RCC-associated mutations, most patients with non-clear cell RCC had no family history or other syndromic features while all patients with clear cell RCC had syndromic features. Additionally, 5% of patients were found to have clinically significant mutations in non-RCC genes. Our findings support broad testing of patients with early onset RCC, especially those with non-clear cell RCC.