Recurrent germline mutation in MSH2 arises frequently de novo

Introduction-An intronic germline mutation in the MSH2 gene, A-->T at nt942 +3, interferes with the exon 5 donor splicing mechanism leading to a mRNA l acking exon 5. This mutation causes typical hereditary non-polyposis colore ctal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previous ly been shown to be enriched in the population of Newfoundland where most f amilies shared a founder mutation. In contrast, in England, haplotypes fail ed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would c onstitute an unexplored predisposition. Methods-We studied 10 families from England, Italy, Hong Kong, and Japan wi th a battery of intragenic and flanking polymorphic single nucleotide and r nicrosatellite markers. Results-Haplotype sharing was not apparent, even within the European and As ian kindreds. Our marker panel was sufficient to detect a major mutation ar ising within the past several thousand generations. Discussion-As a more ancient founder is implausible, we conclude that the A -->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high freq uency. We hypothesise that it arises as a consequence of misalignment at re plication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germ line mutation yet to be detected in a human mismatch repair gene, accountin g for 11% of all known pathogenic MSN2 mutations.