The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer

Steven M. Lipkin, Laura S. Rozek, Gad Rennert, Wei Yang, Peng Chieh Chen, Joseph Hacia, Nathan Hunt, Brian Shin, Steve Fodor, Mark Kokoris, Joel K. Greenson, Eric Fearon, Henry Lynch, Francis Collins, Stephen B. Gruber

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)


Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G→C, resulting in the amino acid substitution D132H) in ∼1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLHI 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G→C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed.

Original languageEnglish
Pages (from-to)694-699
Number of pages6
JournalNature Genetics
Issue number7
Publication statusPublished - 2004 Jul

All Science Journal Classification (ASJC) codes

  • Genetics


Dive into the research topics of 'The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer'. Together they form a unique fingerprint.

Cite this