Prostate cancer is the most common non-cutaneous cancer in US men and among Veterans. Many cases are non-lethal, but prostate cancer remains the 2nd leading cause of cancer death among US men. A major barrier to reducing the incidence of prostate cancer metastasis and death is the lack of an optimal screening strategy to identify men at high risk. Screening with prostate-specific antigen (PSA) testing modestly reduces prostate cancer deaths but increases the morbidity associated with overdiagnosis and overtreatment. Current screening approaches do not adequately distinguish men without prostate cancer or with low-grade prostate cancer amenable to active surveillance from men with clinically significant prostate cancer (csPCa), who need treatment. As a result, guidelines do not recommend universal prostate cancer screening. However, a new paradigm of precision screening might improve the benefit-to-harm ratio of screening by implementing screening strategies tailored to an individual's specific genetic profile. Germline genetic testing has emerged as a powerful predictor for prostate cancer, including csPCa. This includes both rare highly penetrant variants and polygenic risk scores (PRS), which characterize an individual's predisposition to prostate cancer due to common genetic variation. Rare and common genetic variation is now an equally powerful predictor of clinically significant disease as self-reported race or family history. This CSR&D Combined Proof of Concept and Clinical Trial will evaluate the promise of precision risk stratification to identify men most likely to benefit from prostate cancer screening. During the proof-of-concept phase, it will achieve the following: 1) Develop a precision prostate cancer screening intervention consisting of genetic testing for rare variants and a transancestry PRS for delivery to participants and their primary care providers along with individualized, genetic risk-informed screening recommendations. 2) Determine the feasibility of enrolling men aged 55-70, at least 35% of whom are of racial/ethnic minority groups, to a pragmatic randomized clinical trial (RCT) comparing the precision screening intervention to usual care. 3) Perform an interim assessment to determine whether the observed trajectory of prostate biopsy event rates is consistent with rates needed to detect a meaningful between-group difference at the end of the 7-year project period. If feasibility of enrollment and adequate event rates are demonstrated during the proof-of-concept phase, the RCT will continue to the clinical trial phase to test the following co-primary hypotheses: 1) Compared with men in the usual care arm, men in the precision screening arm will have a time-to-diagnosis of clinically significant prostate cancer (csPCa, defined as NCCN classification intermediate risk or higher) that is not inferior by a margin of >30 days over a median 4 years of follow-up; 2) Compared with usual care, men in the precision screening arm...