title: Novel approaches in evaluation of pathogenicity of single-base exonic germline changes involving the mismatch repair genes MLH1 and MSH2 in diagnostics of Lynch syndrome.
abstract: Germline defects in the DNA mismatch repair genes MLH1 and MSH2 are the major cause of hereditary nonpolyposis colon cancer (HNPCC), also called Lynch syndrome. Detection of inherited pathogenic change in their DNA sequence in HNPCC families allows for identification of asymptomatic individuals who require appropriate medical surveillance. However, evaluation of clinical significance of identified DNA alteration is not always straight-forward and some changes maybe classified incorrectly depending on the method used. The aim of this review is to summarize rationale, practice and pitfalls in the characterization of substitutions localized in the exons and outline new experimental and in silico approaches used to determine mutation consequence. Our survey of variants identified in MLH1 and MSH2 genes which were confirmed to cause splicing defect but often appear characterized as missense, nonsense or silent mutations in various databases and publications as well as a list of true missense mutations may serve as a valuable aid for laboratories providing HNPCC diagnosis.
authors.affiliation: Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: M
authors.initials: M
authors.lastname: Gerykova-Bujalkova
authors.forename: T
authors.initials: T
authors.lastname: Krivulcik
authors.forename: Z
authors.initials: Z
authors.lastname: Bartosova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein