Of the MMR genes—MLH1, MSH2, MSH6, PMS2, (and EPCAM, which when mutated inactivates the downstream MSH2)—the first two to be identified, MSH2 and MLH1, were detected through the study of very highly penetrant families with striking aggregations of colorectal cancer, with onset as early as age 40, 30, or even 20 years. The gene discussed is MLH1; the disease is colorectal cancer.