An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer

Lynch syndrome (LS) is the most common inherited disorder predisposing individuals to colorectal cancer (CRC). It results from germline defects in DNA mismatch repair (MMR) genes, which are critical for maintaining genomic integrity. Here, we demonstrate that the expression of the MMR genes MLH1 and PMS2 are significantly reduced in colon tumor tissues from a proband with CRC, potentially resulting from inherited mutations in the MLH1 gene in LS cases. We identified a previously unreported in-frame deletion mutation in the MLH1 gene, classified as a variant of uncertain significance (VUS) due to its undefined role in oncogenesis. The majority of functionally inactive mutants were located in the residues Phe614 to Lys617, which form crucial hydrogen bonds. Taken together, our data reveals a correlation between this mutation and increased susceptibility to LS-associated tumors. The study offers a valuable insight for evaluating cancer susceptibility in carriers of MLH1 mutants, potentially elucidating the functional roles of MLH1 in oncogenesis.