The BARD1 Cys557Ser variant and breast cancer risk in Iceland.

• Published in: PLoS Medicine
• Main Authors: Stacey, Simon N, Sulem, Patrick, Johannsson, Oskar T, Helgason, Agnar, Gudmundsson, Julius, Kostic, Jelena P, Kristjansson, Kristleifur, Jonsdottir, Thora, Sigurdsson, Helgi, Hrafnkelsson, Jon, Johannsson, Jakob, Sveinsson, Thorarinn, Myrdal, Gardar, Grimsson, Hlynur Niels, Bergthorsson, Jon T, Amundadottir, Laufey T, Gulcher, Jeffrey R, Thorsteinsdottir, Unnur, Kong, Augustine, Stefansson, Kari
• Other Authors: deCODE Genetics, Reykjavik, Iceland. [e-mail]
• Format: Article in Journal/Newspaper
• Language: English
• Published: Public Library of Science 2009
• Subjects: Adult; Age of Onset; Aged; Alleles; Amino Acid Substitution; Breast Neoplasms; Carcinoma in Situ; Carcinoma; Ductal; Breast; Intraductal; Noninfiltrating; Lobular; Medullary; Case-Control Studies; Cluster Analysis; Cohort Studies; Female; Founder Effect; Gene Frequency; Genes; BRCA2; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Iceland; Middle Aged; Mutation; Missense; Neoplastic Syndromes; Hereditary; Odds Ratio; Point Mutation; Polymorphism; Single Nucleotide; Risk; Sequence Deletion; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases
• Online Access: http://hdl.handle.net/2336/65453; https://doi.org/10.1371/journal.pmed.0030217

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field 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. METHODS AND FINDINGS: 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 ...