Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer

Rebecca A Barnetson, Nicola Cartwright, Annelot van Vliet, Naila Haq, Kate Drew, Susan Farrington, Nicola Williams, Jon Warner, Harry Campbell, Mary Porteous, Malcolm G Dunlop

Research output: Contribution to journalArticlepeer-review

Abstract

Identification of germline mutations in DNA mismatch repair genes in colorectal cancer probands without an extensive family history can be problematic when ascribing relevance to cancer causation. We undertook a structured assessment of the disease-causing potential of sequence variants identified in a prospective, population-based study of 932 colorectal cancer patients, diagnosed at A p.G67E, MLH1 c.2041G>A p.A681T, and MSH2 c.2634+5G>C were categorized as pathogenic through assimilation of all available data, while 14 variants were categorized as benign (seven MLH1, three MSH2, and four MSH6). Interestingly, there is tentative evidence suggesting a possible protective effect of three variants (MLH1 c.2066A>G pQ689R, c.2146G>A p.V716M, and MSH2 c.965G>A p.G322D). These findings support a causal link with colorectal cancer for several DNA mismatch repair gene variants. However, the majority of missense changes are likely to be inconsequential polymorphisms.
Original languageEnglish
Pages (from-to)367-374
Number of pages8
JournalHuman Mutation
Volume29
Issue number3
DOIs
Publication statusPublished - Mar 2008

Keywords

  • DNA mismatch repair
  • Lynch syndrome
  • HNPCC
  • colorectal cancer
  • MLH1
  • MSH2
  • MSH6

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