In a case-control study of 2 large population- and health system–based cohorts with a total of 636 815 participants, individuals with heterozygous CHEK2 variants had a significantly increased risk for all cancer; breast, kidney, bladder, and prostate cancer; and lymphoid leukemia, although cancer risk was generally lower compared with phenotypically ascertained cohorts. The gene discussed is CHEK2; the disease is prostate cancer.