The BARD1 Cys557Ser variant and breast cancer risk in Iceland.

• Published in: PLoS Medicine
• Main Authors: Simon N Stacey, Patrick Sulem, Oskar T Johannsson, Agnar Helgason, Julius Gudmundsson, Jelena P Kostic, Kristleifur Kristjansson, Thora Jonsdottir, Helgi Sigurdsson, Jon Hrafnkelsson, Jakob Johannsson, Thorarinn Sveinsson, Gardar Myrdal, Hlynur Niels Grimsson, Jon T Bergthorsson, Laufey T Amundadottir, Jeffrey R Gulcher, Unnur Thorsteinsdottir, Augustine Kong, Kari Stefansson
• Format: Article in Journal/Newspaper
• Language: English
• Published: Public Library of Science (PLoS) 2006
• Subjects: Medicine; R; Iceland
• Online Access: https://doi.org/10.1371/journal.pmed.0030217; https://doaj.org/article/514f37664d6e4183ab65a318a37e9f78

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.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 ...