Mutator phenotypes of common polymorphisms and missense mutations in MSH2

Hereditary non-polyposis colorectal cancer (HNPCC) is associated with germl ine mutations in the DNA mismatch repair gene hMSH2 [1], the human homologu e of the Escherichia coli MutS gene. These are mostly nonsense, frameshift or deletion mutations that result in loss of intact protein and complete in activation of DNA mismatch repair. However, cancer is also associated with hMSH2 missense mutations that are merely inferred to be deleterious because they result in non-conservative substitutions of amino acids that are high ly conserved among MutS family proteins. Moreover, sequence polymorphisms e xist in hMSH2 that also change conserved amino acids but whose functional c onsequences and relationship to cancer are uncertain. Here, we show that ye ast strains harboring putative equivalents of three hMSH2 polymorphisms hav e elevated mutation rates. Mutator effects were also observed for yeast equ ivalents of hMSH2 missense mutations found in HNPCC families and in an earl y onset colon tumor. Several distinct phenotypes were observed, indicating that these missense mutations have differential effects on MSH2 function(s) . The results suggest that cancer may be associated with even partial loss of hMSH2 function and they are consistent with the hypothesis that polymorp hisms in hMSH2 might predispose humans to disease.