title: A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.
abstract: BACKGROUND
  An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.
  
  
  METHODS
  We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.
  
  
  RESULTS
  The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.
  
  
  CONCLUSIONS
  We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.
authors: Department of Medical Genetics, University Medical Centre Utrecht, Lundlaan 6, Utrecht, The Netherlands. E.vanRiel@umcutrecht.nl.
authors: Els
authors: E
authors: van Riel
authors: Margreet Gem
authors: MG
authors: Ausems
authors: Frans Bl
authors: FB
authors: Hogervorst
authors: Irma
authors: I
authors: Kluijt
authors: Marielle E
authors: ME
authors: van Gijn
authors: Jeanne
authors: J
authors: van Echtelt
authors: Karen
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authors: Scheidel-Jacobse
authors: Eric Fam
authors: EF
authors: Hennekam
authors: Rein P
authors: RP
authors: Stulp
authors: Yvonne J
authors: YJ
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authors: G Johan A
authors: GJ
authors: Offerhaus
authors: Fred H
authors: FH
authors: Menko
authors: Johan Jp
authors: JJ
authors: Gille