title: Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women.
abstract: BACKGROUND
  BRCA1 and BRCA2 account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance CHEK2 alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population.
  
  
  METHODS
  The 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques.
  
  
  RESULTS
  Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73).
  
  
  CONCLUSIONS
  The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.
authors.affiliation: Program in Cancer Genetics, Department of Oncology, McGill University, Montreal, QC, H2W 1S6, Canada. david.novak@mail.mcgill.ca
authors.forename: David J
authors.initials: DJ
authors.lastname: Novak
authors.forename: Long Qi
authors.initials: LQ
authors.lastname: Chen
authors.forename: Parviz
authors.initials: P
authors.lastname: Ghadirian
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.forename: Phil
authors.initials: P
authors.lastname: Zhang
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rossiny
authors.forename: Guy
authors.initials: G
authors.lastname: Cardinal
authors.forename: André
authors.initials: A
authors.lastname: Robidoux
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
authors.forename: Francois
authors.initials: F
authors.lastname: Rousseau
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D002170:Canada; D064447:Checkpoint Kinase 2; D005260:Female; D018703:Founder Effect; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases