MLH1 heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). This system assembles in a stepwise fashion, with the MutL complex recruited after the the dsDNA mismatch has been identified.Two representative MLH1 variants are described, MLH1 HIS329PRO and MLH1 SER252TER. The MLH1 HIS329PRO variant was identified in a family that fulfilled the Amsterdam criteria (a set of diagnostic criteria used to help identify families likely to carry gene variants predisposing them to hereditary nonpolyposis colorectal cancer (HNPCC)) of HNPCC as well as its identification as a his329-to-pro germline mutation (Vasen et al., 1991, Wang et al. 1997). The mutations' pathogenic significance was supported by the identification of the same missense mutation as a somatic event ('second hit') in colonic tumors of 2 other HNPCC patients who had germline mutations at different sites of the MLH1 gene.The MLH1 SER252TER variant was identified in a colorectal tumor cell line manifesting microsatellite instability (Papadopoulos et al, 1994). Sequence analysis of the cDNA revealed a C-to-A transversion at codon 252, resulting in the substitution of a stop codon for serine.
Loss of function of MLH1 Variants [nucleoplasm]