title: Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations.
abstract: BACKGROUND
  Lynch syndrome, the most frequent hereditary colorectal cancer syndrome, is caused by defects in mismatch repair genes. Genetic testing is important in order to identify mutation carriers who can benefit from intensive surveillance programs. One of the challenges with genetic testing is the interpretation of pathogenicity of detected DNA variants. The aim of this study was to investigate all putative pathogenic variants tested for at the Division of Molecular Medicine, Pathology North, in Newcastle, Australia, to establish whether previous variant classification is in accordance with that recently performed in the InSiGHT collaboration.
  
  
  METHODS
  Prediction programs and available literature were used to classify new variants or variants without classification.
  
  
  RESULTS
  We identified 333 mutation positive families, in which 211 different putative pathogenic mismatch repair mutations were found. Most variants with an InSiGHT classification (141 out of 146) were in accordance with our classification. Five variants were discordant, of which one can definitively be reclassified according to the InSiGHT scheme as class 5. Sixty-four variants had not been classified by InSiGHT, of whom 55 have not been previously reported.
  
  
  CONCLUSIONS
  In conclusion, we found that our classifications were mostly in accordance with the InSiGHT scheme. In addition to already known MMR mutations, we have also presented 55 novel pathogenic or putative pathogenic mutations.
authors.affiliation: Department of Laboratory MedicineChildren's and Women's HealthFaculty of MedicineNorwegian University of Science and Technology7491TrondheimNorway; Department of Pathology and Medical GeneticsSt. Olavs HospitalTrondheim University Hospital7006TrondheimNorway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Sjursen
authors.affiliation: Division of Molecular Medicine Pathology North Newcastle New South Wales Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: McPhillips
authors.affiliation: Division of Molecular MedicinePathology NorthNewcastleNew South WalesAustralia; School of Biomedical Sciences and PharmacyFaculty of Health and MedicineUniversity of NewcastleNewcastleNew South WalesAustralia; Hunter Medical Research InstituteNewcastleNew South WalesAustralia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Department of Laboratory MedicineChildren's and Women's HealthFaculty of MedicineNorwegian University of Science and Technology7491TrondheimNorway; School of Biomedical Sciences and PharmacyFaculty of Health and MedicineUniversity of NewcastleNewcastleNew South WalesAustralia; Hunter Medical Research InstituteNewcastleNew South WalesAustralia; The Cancer DepartmentMøre og Romsdal Hospital TrustMoldeNorway; Department of Research and DevelomentMøre og Romsdal Hospital TrustMoldeNorway.
authors.forename: Bente A
authors.initials: BA
authors.lastname: Talseth-Palmer
keywords: Genetic testing; InSiGHT classification; interpretation of mutations; lynch syndrome; mismatch repair genes; pathogen mutations