title: Genotype and phenotype of a new 2-bp deletion of hMSH2 at codon 233.
abstract: Germline mutations within mismatch repair genes, such as hMSH2, hMLH1, and hMSH6, have been shown to be the hallmark of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The spectrum of tumors associated with mismatch repair gene defects and the possible relationship between genotype and phenotype are still unclear. Therefore, the spectrum of tumors and the possible genotype-phenotype relationship are still under discussion. Here, we 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 expression 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 five tested people at risk, with a high mortality rate and a trend toward lower age of onset in subsequent generations. Finally, a metachronous breast cancer in one patient turned out to be a tumor unrelated to microsatellite instability phenocopy, i.e., a sporadic tumor unrelated to HNPCC that expressed the hMSH2 gene and did not show any microsatellite instability.
authors.affiliation: Department of General Surgery and Human Genetics, University of Göttingen, Germany. dramueller@aol.com
authors.forename: A
authors.initials: A
authors.lastname: Müller
authors.forename: K
authors.initials: K
authors.lastname: Beyser
authors.forename: H
authors.initials: H
authors.lastname: Arps
authors.forename: S
authors.initials: S
authors.lastname: Bolander
authors.forename: H
authors.initials: H
authors.lastname: Becker
authors.forename: J
authors.initials: J
authors.lastname: Rüschhoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002675:Child, Preschool; D003062:Codon; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D051718:MutS Homolog 2 Protein; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D003062:Codon; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein