Some pathogenic BRCA1 mutants do not bind BARD1

Stable Identifier
Reaction [transition]
Homo sapiens
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The heterodimerization of BRCA1 and BARD1 is mediated by sequences encompassing the N-terminal RING domains of both proteins (Wu et al. 1996, Brzovic, Rajagopal et al. 2001, Brzovic, Meza et al. 2001, Morris et al. 2002). Cancer-predisposing mutations in the RING domain of BRCA1 frequently disrupt the formation of the BRCA1:BARD1 complex.

The following BRCA1 mutants identified in cancer patients or in families with the hereditary breast and ovarian cancer syndrome were functionally tested and shown to be unable to bind to BARD1:
BRCA1 M18T (Ransburgh et al. 2010)
BRCA1 C24R (Ransburgh et al. 2010)
BRCA1 C27A (Ransburgh et al. 2010)
BRCA1 T37R (Ransburgh et al. 2010)
BRCA1 C39Y (Ransburgh et al. 2010)
BRCA1 H41A (Ransburgh et al. 2010)
BRCA1 H41R (Ransburgh et al. 2010)
BRCA1 C44F (Ransburgh et al. 2010)
BRCA1 C47G (Ransburgh et al. 2010)
BRCA1 C61G (Wu et al. 1996, Ransburgh et al. 2010)
BRCA1 C64G (Wu et al. 1996, Ransburgh et al. 2010)
BRCA1 C64R (Caleca et al. 2014).

The following BRCA1 mutants were identified in cancer and predicted to be pathogenic. They are annotated as candidate mutants for BARD1 binding deficiency based on sequence similarity with the functionally characterized missense mutants (the same amino acid residue affected by a missense mutation as in a missense mutant shown to be unable to bind to BARD1) or based on the truncation of the RING domain due to frameshift mutations:
BRCA1 Q12Tfs*5
BRCA1 E23Afs*18
BRCA1 E23Rfs*18
BRCA1 E23Vfs*17
Literature References
PubMed ID Title Journal Year
24516540 Characterization of an Italian founder mutation in the RING-finger domain of BRCA1

Bernard, L, Zaffaroni, D, Colombo, M, Sarkar, M, Congregati, C, Magliery, TJ, Ripamonti, CB, Papi, L, Barile, M, Pensotti, V, Peissel, B, Manoukian, S, Tondini, C, Caleca, L, Foglia, C, Radice, P, Putignano, AL

PLoS ONE 2014
11573085 Structure of a BRCA1-BARD1 heterodimeric RING-RING complex

King, MC, Hoyt, DW, Rajagopal, P, Brzovic, PS, Klevit, RE

Nat. Struct. Biol. 2001
11526114 BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions

Meza, JE, Brzovic, PS, Klevit, RE, King, MC

J. Biol. Chem. 2001
8944023 Identification of a RING protein that can interact in vivo with the BRCA1 gene product

Phung, A, Bowcock, AM, Wu, LC, Hwang, LY, Wang, ZW, Baer, R, Yang, MC, Spillman, MA, Xu, XL, Tsan, JT

Nat. Genet. 1996
20103620 Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination

Ishioka, C, Toland, AE, Ransburgh, DJ, Parvin, JD, Chiba, N

Cancer Res. 2010
Normal reaction
Functional status

Loss of function of BRCA1 mutants (BARD1 binding) [nucleoplasm]

Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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