The Von Hippel-Lindau (vHL) gene may be altered as a somatic (acquired) alteration and/or as a germline alteration associated with a rare autosomal dominant inherited cancer syndrome predisposing to a variety of malignant and benign tumors including clear cell renal cell carcinoma (ccRCC). The protein encoded by this gene is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. The VHL C162Y mutation has not been functionally or clinically validated. However, VHL C162F is known to be oncogenic, and therefore VHL C162Y is considered likely oncogenic. According to ClinVar, VHLC162F is also reported as a pathogenic germline variant (https://preview.ncbi.nlm.nih.gov/clinvar/variation/223225/). These results should be interpreted in the clinicopathologic context and appropriate germline genetic workup may be considered if clinically indicated.