Genotype and phenotype of a new 2-bp deletion of hMSH2 at codon 233

Germline mutations within mismatch repair genes, such as hMSH2, hMLH1, and hMSH6, have been shown to be the hallmark of the hereditary nonpolyposis co lorectal cancer (HNPCC) syndrome. The spectrum of tumors associated with mi smatch repair gene defects and the possible relationship between genotype a nd phenotype are still unclear. Therefore, the spectrum of tumors and the p ossible genotype-phenotype relationship are still under discussion. Here, w e report on a family with a new germline mutation in the hMSH2 gene with a 2-bp deletion at codons 232 and 233 leading to a frame shift and a stop at codon 254. Accordingly, immunohistochemistry revealed loss of hMSH2 express ion in colorectal carcinomas of three affected family members. In this one family, there was a high penetrance. Interestingly, mutational screening of the family revealed a high penetrance of the mutation affecting four of fi ve tested people at risk, with a high mortality rate and a trend toward low er age of onset in subsequent generations. Finally, a metachronous breast c ancer in one patient turned out to be a tumor unrelated to microsatellite i nstability phenocopy, i.e., a sporadic tumor unrelated to HNPCC that expres sed the hMSH2 gene and did not show any microsatellite instability.