title: The BARD1 Cys557Ser variant and breast cancer risk in Iceland.
abstract: BACKGROUND
  Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.
  
  
  RESULTS
  The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.
  
  
  CONCLUSIONS
  Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
authors.affiliation: deCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.is
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Oskar T
authors.initials: OT
authors.lastname: Johannsson
authors.forename: Agnar
authors.initials: A
authors.lastname: Helgason
authors.forename: Julius
authors.initials: J
authors.lastname: Gudmundsson
authors.forename: Jelena P
authors.initials: JP
authors.lastname: Kostic
authors.forename: Kristleifur
authors.initials: K
authors.lastname: Kristjansson
authors.forename: Thora
authors.initials: T
authors.lastname: Jonsdottir
authors.forename: Helgi
authors.initials: H
authors.lastname: Sigurdsson
authors.forename: Jon
authors.initials: J
authors.lastname: Hrafnkelsson
authors.forename: Jakob
authors.initials: J
authors.lastname: Johannsson
authors.forename: Thorarinn
authors.initials: T
authors.lastname: Sveinsson
authors.forename: Gardar
authors.initials: G
authors.lastname: Myrdal
authors.forename: Hlynur Niels
authors.initials: HN
authors.lastname: Grimsson
authors.forename: Jon T
authors.initials: JT
authors.lastname: Bergthorsson
authors.forename: Laufey T
authors.initials: LT
authors.lastname: Amundadottir
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gulcher
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D002278:Carcinoma in Situ / Q000208:ethnology / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000208:ethnology / Q000235:genetics; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000208:ethnology / Q000235:genetics; D018275:Carcinoma, Lobular / Q000208:ethnology / Q000235:genetics; D018276:Carcinoma, Medullary / Q000208:ethnology / Q000235:genetics; D016022:Case-Control Studies; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D008875:Middle Aged; D020125:Mutation, Missense; D009386:Neoplastic Syndromes, Hereditary / Q000208:ethnology / Q000235:genetics*; D016017:Odds Ratio; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology
chemical_list: D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases