MLH1 (MutL protein homolog 1) is a tumor suppressor that dimerizes with PMS2 to form a component of the DNA mismatch repair system. MLH1 promoter methylation and mutations are associated with colorectal cancer. Simple variants in MLH1 are seen in about 1% of all tumors, including about 4% of colorectal cancers (CRC), 3% of skin cancers, and 2% of endometrial cancers. Germline mutations in MLH1 cause Lynch syndrome and CMMR-D. The presence of MLH1 mutations indicates microsatellite instability, which correlates with a better prognosis in CRC and response to immunotherapy.