MLH1

About MLH1

MLH1 on chromosome 3p22.2 encodes a key component of the DNA mismatch repair system, forming the MutL alpha complex with PMS2 to correct base mispairs and small insertion or deletion loops introduced during DNA replication. Germline MLH1 variants are a major cause of Lynch syndrome, formerly called hereditary nonpolyposis colorectal cancer, which is the most common inherited colorectal cancer syndrome. Lynch syndrome raises lifetime risk of colorectal and endometrial cancer substantially, and also increases the risk of ovarian, gastric, small bowel, urothelial, pancreatic, biliary, and brain tumors, as well as sebaceous skin tumors in the Muir Torre variant. The syndrome is named after Henry Lynch, who described affected families in the 1960s, and MLH1 was identified as a cause in 1994. Tumors lacking mismatch repair show microsatellite instability, which can be detected by molecular testing or by immunohistochemistry for the repair proteins, and many centers screen all colorectal and endometrial cancers this way. Loss of MLH1 in sporadic tumors is often due to promoter methylation rather than inherited variants, and BRAF V600E testing helps make this distinction. Mismatch repair deficient cancers frequently respond well to PD 1 immune checkpoint inhibitors, and surveillance and risk reducing options are offered to identified carriers.