title: Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.
abstract: OBJECTIVE
  Inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2.
  
  
  METHODS
  Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results.
  
  
  RESULTS
  None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions.
  
  
  CONCLUSIONS
  Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein.
authors.affiliation: Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Ollila
authors.forename: Laura
authors.initials: L
authors.lastname: Sarantaus
authors.forename: Reetta
authors.initials: R
authors.lastname: Kariola
authors.forename: Philip
authors.initials: P
authors.lastname: Chan
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
authors.forename: Maija
authors.initials: M
authors.lastname: Kohonen-Corish
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Marc
authors.initials: M
authors.lastname: Greenblatt
authors.forename: Minna
authors.initials: M
authors.lastname: Nyström
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D004260:DNA Repair; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein