Context: Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is caused by mutations in the mismatch repair genes and confers an extraordinarily high risk of colorectal, endometrial, and other cancers. However, while carriers of these mutations should be identified, counseled, and offered clinical surveillance, at present the mutations are not tested for in mutation analyses. Objective: To describe the prevalence of a large genomic deletion encompassing exons 1 to 6 of the MSH2 gene that is widespread in the US population as a result of a founder effect. Design, Setting, and Patients: Ongoing genealogical and historical study conducted to assess the origin and spread of an MSH2 mutation previously identified in 9 apparently unrelated families with putative HNPCC and living in widely different geographic locations in the United States. Main Outcome Measures: Classification of family members as carriers or noncarriers of the MSH2 mutation; spread of the mutation across the continental United States. Results: To date, 566 family members of the 9 probands have been identified to be at risk and counseled; 137 of these have been tested, and 61 carry the founder mutation. Three families have been genealogically shown to descend from a German immigrant family that arrived and first settled in Pennsylvania in the early 1700s. Movements of branches of the family from Pennsylvania through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah, Texas, and California have been documented, and carriers of the mutation have already been diagnosed in 14 states. In contrast, the deletion was not found among 407 European and Australian families with HNPCC. Conclusion: The postulated high frequency and continent-wide geographic distribution of a cancer-predisposing founder mutation of the MSH2 gene in a large, outbred (as opposed to genetically isolated) population, and the ease with which the mutation can be detected, suggest that the routine testing of individuals at risk for HNPCC in the United States should include an assay for this mutation until more is learned about its occurrence.
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