KLK3 and Familial prostate cancer: • Training cohort: gene expression assay in combination with SOC (AUC = 0.77) significantly improved performance SOC alone (AUC=0.66) for predicting high-grade PCa (HGPCa, GS ≥ 7) from low-grade PCa (GS = 6) and benign disease.• Validation cohort: compared with the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) (AUC = 0.62) and PSA alone (AUC = 0.55), Gene Expression Assay (AUC = 0.71) demonstrated improved performance.• Using a predefined cut point, 27% of biopsies would have been avoided, missing only 5% of patients with dominant pattern 4 high-risk GS7 disease.