To characterize the frequency of germline alterations in a potentially enriched renal cell carcinoma (RCC) population, including early onset (EO), bilateral multifocal (BMF), or those with a family history of renal cancer (FRC).

We identified 380 consecutive patients referred with a new diagnosis of a renal mass without a personal or family history of a hereditary RCC syndrome, of which 245 underwent a germline genetic panel and were included in the analysis. The predictive accuracy of 3 clinical enrichment features (EO, BMF, and FRC) and the likelihood of identifying a pathogenic/likely pathogenic variant were assessed.

Of the 245 patients, 217 had at least 1 of the 3 enrichment features, including 106 with EO, 144 with BMF, and 62 with FRC. Panel results were positive in 33 (13.5%) patients, negative in 171 (69.8%), or reported a variant of uncertain significance in 41 (16.7%). More than 1 enrichment feature increased the proportion of positive results: 7.1% with no features, 11.3% with 1 feature, 16.4% with 2 features, and 36.4% with 3 features. For each additional enrichment feature, the odds of identifying a germline variant increase by nearly 2-fold (odds ratio = 1.82 [95% confidence interval: 1.10-3.05] P = .02). Female sex was also predictive of positive panel results (odds ratio = 2.80 [95% confidence interval: 1.24-6.67] P = .015) on multivariate analysis.

Patients presenting with EO, BMF, or FRC are enriched populations with more frequent positive germline RCC alterations. The odds of a germline alteration nearly double with each additional enrichment feature. These findings support the use of germline gene panel testing in these populations.