This is particularly striking as clinically actionable variants in mismatch repair genes, including PMS2 and MSH2, offer potential clinical implications for probands with early-onset colorectal cancer to support therapeutic decision-making (e.g., immunotherapy for localized and metastatic diseases) as well as for at-risk family members who may need to initiate disease surveillance at younger ages, at more frequent intervals, and at extracolonic sites. The gene discussed is MSH2; the disease is colorectal cancer.