Case-control study for genomic ascertainment of CHEK2-related cancer predisposition

There is clear evidence that deleterious germline variants in CHEK2 increase risk for breast and prostate cancer. There is limited or conflicting evidence for other cancers. A case-control study using 2 electronic health record-linked and exome-sequenced biobanks (UK Biobank and Geisinger MyCode; together 636,815 participants) quantified the prevalence as well as cancer risk and survival associated with CHEK2 germline pathogenic and likely pathogenic variants when ascertained genomically. Individuals with heterzygous CHEK2 variants had a significantly increased risk for all cancers; breast, kidney, bladder, and prostate cancer; and lymphoid leukemia, although cancer risk was generally lower compared with phenotypically ascertained cohorts. There were no significant differences in survival between CHEK2 case participants with cancer versus control participants with cancer. The authors conclude that these findings suggest that the method of ascertainments matters when estimating risk and should be considered in clinical decision-making.