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A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome
  1. M Clendenning1,
  2. L Senter1,
  3. H Hampel1,
  4. K Lagerstedt Robinson2,
  5. S Sun3,
  6. D Buchanan4,
  7. M D Walsh4,
  8. M Nilbert5,
  9. J Green6,
  10. J Potter7,
  11. A Lindblom2,
  12. A de la Chapelle1
  1. 1
    Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
  2. 2
    Karolinska Institute, Department of Molecular Medicine, Stockholm, Sweden
  3. 3
    Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, USA
  4. 4
    Familial Cancer Laboratory, Queensland Institute of Medical Research, Herston, Australia
  5. 5
    Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden
  6. 6
    Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John’s, Newfoundland, Canada
  7. 7
    Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  1. Professor A de la Chapelle, Human Cancer Genetics, Room 804, Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210, USA; albert.delachapelle{at}


Background: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences.

Methods: Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis.

Results: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency <0.05) at a single nucleotide polymorphism (SNP) in exon 11, and have been shown to possess a short common haplotype, allowing us to calculate that the mutation arose around 1625 years ago (65 generations; 95% confidence interval 22 to 120).

Conclusion: Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are >10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands’ families, would suggest that this is a prevalent mutation with reduced penetrance.

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  • Competing interests: None declared.

  • Patient consent: Informed consent was obtained from the patients for publication of this report.