Pathogenic PMS2 variants present reduced penetrance for Lynch syndrome cancers compared to other mismatch repair genes

PurposeScreening for Lynch syndrome in the general population aims to prevent and detect cancers early. However, current clinical guidelines for those with pathogenic variants are largely based on studies of patients with cancer or strong family history. The objective of this study was to determine the risk of cancer associated with pathogenic variants in MLH1, MSH2, MSH6, or PMS2 in the general population. MethodsThis retrospective case-control study utilizes Helix Research NetworkTM data from 216,095 participants across nine US health systems. Variant interpretation was performed following the ACMG-AMP guidelines. Clinical diagnoses were identified from electronic health records for 11 cancer types associated with Lynch syndrome, including colorectal and endometrial cancers. ResultsIndividuals with pathogenic variants in PMS2 had a small increase in risk for all 11 Lynch syndrome-associated cancers with Hazard Ratio (HR) of 1.6 (95% CI: 0.9-2.7) compared to those without a pathogenic variant. The increase in risk was also small when restricting the analysis to colorectal cancer with HR of 4.4 (2.1-9.3). This increase in colorectal cancer risk was predominantly observed after age 60, 10 years after USPSTF guidelines recommend starting colonoscopies for the average population. Up to age 60, 2.3% of individuals with PMS2 pathogenic variants were diagnosed with colorectal cancer, closer to the general population (0.5%) than those with MLH1 (44.4%), MSH2 (33.7%) or MSH6 (6.6%) pathogenic variants. For 100,000 individuals screened for PMS2, 875 additional colonoscopies would be performed, which would prevent or detect early 2.9 colorectal cancers. ConclusionThis analysis across nine health systems highlights the low clinical utility of genomic screening for PMS2 variants in the general population.