title: A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.
abstract: 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.
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.affiliation: Department of Pathology, McGill University, Montreal, Quebec, Canada Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Baker
authors.affiliation: Department of Software and Information Technology Engineering, École de technologie supérieure, Montreal, Quebec, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGuffin
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Couillard
authors.affiliation: Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gologan
authors.affiliation: Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Marcus
authors.affiliation: Department of Pediatrics and Child Health and Department of Biochemistry and Medical Genetics, Winnipeg, Manitoba, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Chodirker
authors.affiliation: Department of Pediatrics and Child Health and Department of Biochemistry and Medical Genetics, Winnipeg, Manitoba, Canada.
authors.forename: Albert
authors.initials: A
authors.lastname: Chudley
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Camelia
authors.initials: C
authors.lastname: Stefanovici
authors.affiliation: INSERM U768, Hôpital Necker, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.affiliation: Robarts Research Institute and Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
authors.forename: Bing-Jian
authors.initials: BJ
authors.lastname: Feng
authors.affiliation: Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.affiliation: Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotechnologie Avanzate, University of Naples-Federico II, Naples, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: De Rosa
authors.affiliation: USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.affiliation: Division Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
authors.affiliation: Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada First Nations and Inuit Health Branch, Health Canada (Quebec Region), Montreal, Quebec, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Young
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Chong
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, Canada Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Tischkowitz
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, Canada Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D018703:Founder Effect; D015870:Gene Expression; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes
keywords: constitutional mismatch repair deficiency (CMMRD); gene expression; genotype-phenotype; splice site; tumor suppression