title: The Norwegian PMS2 founder mutation c.989-1G > T shows high penetrance of microsatellite instable cancers with normal immunohistochemistry.
abstract: BACKGROUND
  Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions.
  
  
  METHODS
  All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm.
  
  
  RESULTS
  Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers.
  
  
  CONCLUSIONS
  The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males.
authors.affiliation: Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway ; Section of Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Eli Marie
authors.initials: EM
authors.lastname: Grindedal
authors.affiliation: Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Aarset
authors.affiliation: Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway.
authors.forename: Inga
authors.initials: I
authors.lastname: Bjørnevoll
authors.affiliation: Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway.
authors.forename: Elin
authors.initials: E
authors.lastname: Røyset
authors.affiliation: Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway ; Section of Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Lovise
authors.initials: L
authors.lastname: Mæhle
authors.affiliation: Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway ; Section of Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Astrid
authors.initials: A
authors.lastname: Stormorken
authors.affiliation: Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway ; Section of Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Heramb
authors.affiliation: Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway ; Section of Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Heidi
authors.initials: H
authors.lastname: Medvik
authors.affiliation: Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Møller
authors.affiliation: Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway ; Department of Laboratory Medicine Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Sjursen
keywords: Expression; Immunohistochemistry; Lynch syndrome; Microsatellite instability; PMS2; Penetrance