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J Med Genet. 2005 August; 42(8): 633–638.
PMCID: PMC1736120

Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer

Abstract

Background: BRCA1 associated RING domain protein (BARD1) was originally identified due to its interaction with the RING domain of BRCA1. BARD1 is required for S phase progression, contact inhibition and normal nuclear division, as well as for BRCA1 independent, p53 dependent apoptosis.

Methods: To investigate whether alterations in BARD1 are involved in human breast and ovarian cancer, we used single strand conformation polymorphism analysis and sequencing on 35 breast tumours and cancer cell lines and on 21 ovarian tumours.

Results: Along with the G2355C (S761N) missense mutation previously identified in a uterine cancer, we found two other variants in breast cancers, T2006C (C645R) and A2286G (I738V). The T2006C (C645R) mutation was also found in one ovarian tumour. A variant of uncertain consequence, G1743C (C557S), was found to be homozygous or hemizygous in an ovarian tumour. Eleven variants of BARD1 were characterised with respect to known functions of BARD1. None of the variants appears to affect localisation or interaction with BRCA1; however, putative disease associated alleles appear to affect the stability of p53. These same mutations also appear to abrogate the growth suppressive and apoptotic activities of BARD1.

Conclusions: These activities allowed us to identify one of the rare variants (A2286G; I738V) as a neutral polymorphism rather than a detrimental mutation, and suggested that G1743C (C557S) is not a polymorphism but may contribute to the cancer phenotype.

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