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A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype
  1. Lili Li1,2,
  2. Nancy Hamel1,3,
  3. Kristi Baker4,5,
  4. Michael J McGuffin6,
  5. Martin Couillard1,7,
  6. Adrian Gologan8,
  7. Victoria A Marcus9,
  8. Bernard Chodirker10,
  9. Albert Chudley10,
  10. Camelia Stefanovici11,
  11. Anne Durandy12,
  12. Robert A Hegele13,
  13. Bing-Jian Feng14,
  14. David E Goldgar14,
  15. Jun Zhu15,
  16. Marina De Rosa16,
  17. Stephen B Gruber17,
  18. Katharina Wimmer18,
  19. Barbara Young19,20,
  20. George Chong2,8,
  21. Marc D Tischkowitz1,2,7,21,
  22. William D Foulkes1,2,3,7
  1. 1Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
  2. 2Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  3. 3Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada
  4. 4Department of Pathology, McGill University, Montreal, Quebec, Canada
  5. 5Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
  6. 6Department of Software and Information Technology Engineering, École de technologie supérieure, Montreal, Quebec, Canada
  7. 7Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
  8. 8Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada
  9. 9Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada
  10. 10Department of Pediatrics and Child Health and Department of Biochemistry and Medical Genetics, Winnipeg, Manitoba, Canada
  11. 11Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
  12. 12INSERM U768, Hôpital Necker, Paris, France
  13. 13Robarts Research Institute and Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
  14. 14Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
  15. 15Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
  16. 16Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotechnologie Avanzate, University of Naples—Federico II, Naples, Italy
  17. 17USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  18. 18Division Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Innsbruck, Austria
  19. 19Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
  20. 20First Nations and Inuit Health Branch, Health Canada (Quebec Region), Montreal, Quebec, Canada
  21. 21Department of Medical Genetics, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr William D Foulkes, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, 3755 Cote Ste Catherine Road, Montreal, QC, Canada H3T 1E2; william.foulkes{at}


Background Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec.

Methods Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype–phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis.

Results This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s.

Conclusions Our genotype–phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.

  • constitutional mismatch repair deficiency (CMMRD)
  • genotype-phenotype
  • tumor suppression
  • gene expression
  • splice site

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