The MLH1 variants p.Arg265Cys and p.Lys618Ala affect protein stability while p.Leu749Gln affects heterodimer formation.
Germline mutations in the mismatch repair genes lead to the Lynch syndrome/ HNPCC, and genetic testing is offered to identify individuals at risk of developing this disease. About a third of all genetic alterations detected in the mismatch repair gene MutL homolog 1 (MLH1) are missense variants. The majority of these variants are of equivocal clinical significance. In this report, we investigate the molecular basis of the pathogenicity of three missense variants localized to distinct functional domains. Our results demonstrate that the MLH1 variants p.Arg265Cys (c.793C>T) and p.Lys618Ala (c.1852_1853AA>GC) significantly decrease the stability of the protein, while another missense variant p.Leu749Gln (c.2246T>A) is able to compromise heterodimerization of the MLH1-PMS2 complex.
Perera
Sheron
S
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Bapat
Bharati
B
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics*; D019295:Computational Biology; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D004926:Escherichia coli; D029968:Escherichia coli Proteins / Q000737:chemistry; D045325:HCT116 Cells; D006207:Half-Life; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D050505:Mutant Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C501486:MLH1 protein, human; C074770:MutL protein, E coli; D050505:Mutant Proteins; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D045643:DNA Repair Enzymes