J Med Genet 41:e114 doi:10.1136/jmg.2004.020669
  • Online mutation report

Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer

  1. S-M Karppinen,
  2. K Heikkinen,
  3. K Rapakko,
  4. R Winqvist
  1. Department of Clinical Genetics, Oulu University Hospital/University of Oulu, PO Box 24, FIN-90029 OYS, Finland
  1. Correspondence to:
 R Winqvist
 Department of Clinical Genetics, Oulu University Hospital/University of Oulu, PO Box 24, FIN-90029 OYS, Finland;
  • Received 10 May 2004
  • Accepted 10 May 2004

Approximately 5–10% of all breast and ovarian cancers are thought to arise from a hereditary predisposition to the disease,1BRCA1 and BRCA2 being the most important susceptibility genes.2,3 Genomic alterations in BRCA1 are found in 40–50% of families with a high incidence of breast cancer (six or more cases), and in a majority (75–80%) of the families that display both breast and ovarian cancers.4,5 However, a significant portion of genetic aberrations predisposing to these cancers, especially in relatively small risk families, still remains unexplained.6,7 BRCA1 interacts with a variety of proteins and is involved in multiple cellular processes including DNA repair, transcription, and checkpoint control.8–10 In attempts to identify new breast and ovarian cancer susceptibility genes, much research has focused on BRCA1 associated proteins.

BARD1 was originally identified through its interaction with BRCA1, with which it has a closely related domain structure.11 Both proteins possess an N-terminal RING finger motif and two BRCA1 C-terminal (BRCT) domains present in numerous proteins involved in DNA repair and cell cycle regulation.11 The functionally important BARD1/BRCA1 heterodimer formation is mediated by the RING finger motifs and has also been shown to markedly increase the stability of both proteins.11–13 The finding of breast cancer associated mutations within the RING finger domain of BRCA1, disrupting BRCA1/BARD1 interaction,11,14 and the occurrence of BARD1 missense mutations in breast cancer patients,15–17 implies participation of BARD1 in BRCA1 mediated tumour suppression. BARD1, unlike BRCA1, also contains a centrally located sequence of three ankyrin repeats11 that are found in many proteins involved in transcriptional regulation.18

Colocalisation of BARD1 with BRCA1 and RAD51 in response to DNA damage indicates a role in DNA repair,19,20 which is supported by the recent …