title: Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.
abstract: BACKGROUND
  Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases.
  
  
  OBJECTIVE
  To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation.
  
  
  METHODS
  Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria.
  
  
  RESULTS
  Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations.
  
  
  CONCLUSIONS
  Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability.
authors.affiliation: Department of Pathology and Medical Genetics, St Olavs University Hospital, Trondheim, Norway. wenche.sjursen@stolav.no
authors.forename: Wenche
authors.initials: W
authors.lastname: Sjursen
authors.forename: Bjørn Ivar
authors.initials: BI
authors.lastname: Haukanes
authors.forename: Eli Marie
authors.initials: EM
authors.lastname: Grindedal
authors.forename: Harald
authors.initials: H
authors.lastname: Aarset
authors.forename: Astrid
authors.initials: A
authors.lastname: Stormorken
authors.forename: Lars F
authors.initials: LF
authors.lastname: Engebretsen
authors.forename: Christoffer
authors.initials: C
authors.lastname: Jonsrud
authors.forename: Inga
authors.initials: I
authors.lastname: Bjørnevoll
authors.forename: Per Arne
authors.initials: PA
authors.lastname: Andresen
authors.forename: Sarah
authors.initials: S
authors.lastname: Ariansen
authors.forename: Liss Anne S
authors.initials: LA
authors.lastname: Lavik
authors.forename: Bodil
authors.initials: B
authors.lastname: Gilde
authors.forename: Inger Marie
authors.initials: IM
authors.lastname: Bowitz-Lothe
authors.forename: Lovise
authors.initials: L
authors.lastname: Maehle
authors.forename: Pål
authors.initials: P
authors.lastname: Møller
mesh_terms: D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D006579:Heterozygote; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009664:Norway; D012680:Sensitivity and Specificity
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein