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Determining the frequency of de novo germline mutations in DNA mismatch repair genes
  1. Aung Ko Win1,
  2. Mark A Jenkins1,
  3. Daniel D Buchanan2,
  4. Mark Clendenning2,
  5. Joanne P Young2,3,
  6. Graham G Giles1,4,
  7. Jack Goldblatt5,
  8. Barbara A Leggett6,7,
  9. John L Hopper1,
  10. Stephen N Thibodeau8,
  11. Noralane M Lindor9
  1. 1Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health,The University of Melbourne, Parkville, Victoria, Australia
  2. 2Familial Cancer Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia
  3. 3School of Medicine, University of Queensland, Herston, Queensland, Australia
  4. 4Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Victoria, Australia
  5. 5Genetic Services of Western Australia and School of Paediatrics and Child Health, University of Western Australia, Perth, Australia
  6. 6Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Brisbane, Australia
  7. 7Conjoint Gastroenterology Laboratory, Pathology Queensland, Clinical Research Centre of Royal Brisbane & Women's Hospital Research Foundation, Queensland Institute of Medical Research, Herston, Queensland, Australia
  8. 8Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  9. 9Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Noralane M Lindor, Department of Medical Genetics, E7B, Mayo Foundation, Rochester, MN 55905, USA; nlindor{at}


Background Carriers of a germline mutation in a DNA mismatch repair (MMR) gene—that is, persons with Lynch syndrome—have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry.

Methods Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband.

Results Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6.

Conclusion De novo MMR gene mutations are uncommon causes of Lynch syndrome.

  • De novo mutation
  • mismatch repair
  • colorectal cancer
  • Lynch syndrome
  • genetics
  • epidemiology
  • gastroenterology
  • oncology
  • cancer: colon
  • genetic screening/counselling
  • cancer: prostate
  • genetic epidemiology

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  • Funding This work was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and Principal Investigators of Australasian Colorectal Cancer Family Registry (U01 CA097735) and Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. Authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.

  • Competing interests None.

  • Ethics approval Written informed consent was obtained from all study participants, and the study protocol was approved at each Colon Cancer Family Registry center.

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