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

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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. Hum Mutat 29(3), 367–374, 2008.