title: Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer.
abstract: OBJECTIVE
  BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is unclear.
  
  
  METHODS
  We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Thr1915Met). [corrected] We evaluated risk of breast and/or ovarian cancer by these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years and in a case-control study of 1,201 breast cancer cases and 4,120 controls.
  
  
  RESULTS
  We found no association between heterozygosity or homozygosity for any of the nine polymorphisms and risk of breast and/or ovarian cancer in either study. We had 80% power to exclude hazard/odds ratios for heterozygotes and/or homozygotes for all nine missense polymorphisms above 1.3 to 3.3 in the prospective study, and above 1.2 to 3.2 in the case-control study.
  
  
  CONCLUSIONS
  Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms.
authors: Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark.
authors: Sarah Louise
authors: SL
authors: Dombernowsky
authors: Maren
authors: M
authors: Weischer
authors: Jacob Johannes
authors: JJ
authors: Freiberg
authors: Stig Egil
authors: SE
authors: Bojesen
authors: Anne
authors: A
authors: Tybjaerg-Hansen
authors: Børge Grønne
authors: BG
authors: Nordestgaard
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors