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Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers
  1. Wenche Sjursen1,2,
  2. Bjørn Ivar Haukanes3,
  3. Eli Marie Grindedal4,
  4. Harald Aarset1,
  5. Astrid Stormorken5,
  6. Lars F Engebretsen3,
  7. Christoffer Jonsrud6,
  8. Inga Bjørnevoll1,
  9. Per Arne Andresen7,
  10. Sarah Ariansen7,
  11. Liss Anne S Lavik1,
  12. Bodil Gilde1,
  13. Inger Marie Bowitz-Lothe5,
  14. Lovise Mæhle4,
  15. Pål Møller4
  1. 1Department of Pathology and Medical genetics, St Olavs University Hospital, Trondheim, Norway
  2. 2Department of Laboratory Medicine Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway
  3. 3Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  4. 4Department of medical genetics, Oslo University Hospital, Radiumhospitalet, Oslo, Norway
  5. 5Department of Medical Genetics, Oslo University Hospital, Ullevål, Norway
  6. 6University Hospital of North Norway, Division of Child and Adolescent Health, Department of Medical Genetics, Tromsø, Norway
  7. 7Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  1. Correspondence to Dr Wenche Sjursen, Department of Pathology and Medical Genetics, Erling Skjalgssons gt 1, St Olavs University Hospital, 7006 Trondheim, Norway; wenche.sjursen{at}


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.

Conclusion 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.

  • MMR gene mutations
  • lynch syndrome
  • Amsterdam criteria
  • Bethesda criteria
  • clinical genetics
  • molecular genetics
  • cancer: colon

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  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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