title: Pathogenicity of A600V variant in exon 12 of the MSH2 gene detected in a Japanese kindred with Lynch syndrome.
abstract: Lynch syndrome is caused by germline mutations of the DNA mismatch repair genes. Missense mutations are often difficult to evaluate as pathogenic. Previously, we reported a missense mutation in exon 12 at codon 600 of the MSH2 gene, causing a substitution of GTT (Val) for GCT (Ala) in a 35-year-old-man with rectal cancer, while the pathogenicity of this mutation is still unclear. In this report, we confirm the same mutation in his 66-year-old mother who had cecal cancer. PCR/direct sequencing analysis of peripheral blood lymphocytes revealed the same missense mutation in exon 12 at codon 600 of the MSH2 gene. The wave height of the capillary sequencer from the wild-type allele was decreased in tumor tissue, indicating loss of heterozygosity in the wild-type allele. Analysis of the tumor showed microsatellite instability high and loss of MSH2 protein expression. This sequence variant has not been reported in another family. This mutation is considered to play a significant and causative role in Lynch syndrome.
authors.affiliation: Department of Surgery, Jichi Medical University, 3311-1 Yakushiji Shimotsuke, Tochigi 329-0498, Japan. miyakura@jichi.ac.jp
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyakura
authors.forename: Kokichi
authors.initials: K
authors.lastname: Sugano
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nomizu
authors.forename: Alan
authors.initials: A
authors.lastname: Lefor
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yasuda
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000328:Adult; D000368:Aged; D002430:Cecal Neoplasms / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012004:Rectal Neoplasms / Q000235:genetics
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein