LS is caused by heterozygous germline inactivating variations in one of the four key DNA MMR genes: MLH1, MSH2, MSH6, and PMS2. In 2015, MLH1, MSH2, MSH6, and PMS2 accounted for 40%, 34%, 18%, and 8%, respectively, of the 3000 unique germline sequence variants of MMR genes deposited in the International Society for Gastrointestinal and Hereditary Tumours (InSiGHT) database [171]. This evidence concerns the gene MLH1 and Leigh syndrome.