{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:11:06Z","timestamp":1791040266970,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2011,8,11]],"date-time":"2011-08-11T00:00:00Z","timestamp":1313020800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. MMR recognizes and repairs DNA mismatches and small insertion\/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline <jats:italic>MSH2 c.1A&gt;C<\/jats:italic> variant which alters the translation initiation codon. Mutations affecting the <jats:italic>MSH2<\/jats:italic> start codon have been described previously for LS\u2010related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS. Therefore, the pathogenicity of start codon variants remains undefined. Loss of the <jats:italic>MSH2<\/jats:italic> start codon has been predicted to result in a truncated protein translated from a downstream in\u2010frame AUG that would lack the first 25 amino acids. We therefore purified recombinant MSH2(N\u039425)\u2010MSH6 and MSH2(N\u039425)\u2010MSH3 to examine their DNA lesion recognition and adenosine nucleotide processing functions <jats:italic>in vitro<\/jats:italic>. We found that the MSH2(N\u039425) mutant confers distinct biochemical defects on MSH2\u2010MSH6, but does not have a significant effect on MSH2\u2010MSH3. We confirmed that expression of the <jats:italic>MSH2 c.1A&gt;C<\/jats:italic> cDNA results in the production of multiple protein products in human cells that may include the truncated and full\u2010length forms of MSH2. An <jats:italic>in vivo<\/jats:italic> MMR assay revealed a slight reduction in MMR efficiency in these cells. These data suggest that mutation of the <jats:italic>MSH2<\/jats:italic> initiation codon, while not a strong, high\u2010risk disease allele, may have a moderate impact on disease phenotype. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/mc.20838","type":"journal-article","created":{"date-parts":[[2011,8,11]],"date-time":"2011-08-11T14:14:04Z","timestamp":1313072044000},"page":"647-658","source":"Crossref","is-referenced-by-count":19,"title":["The predicted truncation from a cancer\u2010associated variant of the <i>MSH2<\/i> initiation codon alters activity of the MSH2\u2010MSH6 mismatch repair complex"],"prefix":"10.1002","volume":"51","author":[{"given":"Jennifer L.","family":"Cyr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham 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