The prospective cohort enrolled patients with HCC at a tertiary hospital in Philadelphia, PA, and 1.8% of patients were found to have P/LP germline variants in high penetrance genes BRCA2, MSH6, and PMS2. In addition, a significant enrichment of P/LP variants in moderate penetrance genes BRIP1 and FANCA was observed when comparing HCC patients with general population rates. This evidence concerns the gene MSH6 and hepatocellular carcinoma.