Defective BARD1 does not bind BRCA1

Stable Identifier
R-HSA-9699163
Type
Reaction [transition]
Species
Homo sapiens
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The N-terminal RING domain and C-terminal BRCT repeats of BARD1 contribute to its binding to BRCA1 (Simons et al. 2006). While not frequently reported in cancer, missense mutations in these two regions of BARD1 affect BARD1 function in homology directed repair (HDR) by impairing its interaction with BRCA1 and may potentially contribute to hereditary breast and ovarian cancer (Lee et al. 2015).

The following BARD1 missense mutants have been reported in hereditary breast and ovarian cancer and shown to be impaired in their interaction with BRCA1 and in HDR:
BARD1 C53W (Lee et al. 2015; the C53W substitution produces an insoluble BARD1 protein)
BARD1 C71Y (Morris et al. 2002; Lee et al. 2015; the C71Y substitution produces an insoluble BARD1 protein)
BARD1 G623E (Lee et al. 2015).

The following BARD1 mutants impaired in their ability to bind to BRCA1 have been clinically reported but not in cancer samples and are annotated as candidates:

BARD1 W34R (Lee et al. 2015 - studied as a synthetic mutant, but is in ClinGen Allele Registry, Pawliczek et al. 2018)
BARD1 L44R (Morris et al. 2002, Lee et al. 2015 - studied as a synthetic mutant, but is in ClinGen Allele Registry, Pawliczek et al. 2018)
BARD1 C50G (Xia et al. 2003)
BARD1 C83G (Xia et al. 2003)

The following BARD1 mutants reported in cancer and predicted to be pathogenic have not been tested for their ability to bind to BRCA1 but share sequence similarity with functionally characterized BARD1 mutants:
BARD1 H68Y (similar to functionally characterized synthetic mutant BARD1 H68A, described in Xia et al. 2003)
BARD1 G632W (similar to functionally characterized cancer mutant BARD1 G623E, described in Lee et al. 2015).

Literature References
PubMed ID Title Journal Year
26350354 Functional Analysis of BARD1 Missense Variants in Homology-Directed Repair of DNA Double Strand Breaks

Lee, C, Banerjee, T, Gillespie, J, Ceravolo, A, Parvinsmith, MR, Starita, LM, Fields, S, Toland, AE, Parvin, JD

Hum. Mutat. 2015
30311374 ClinGen Allele Registry links information about genetic variants

Pawliczek, P, Patel, RY, Ashmore, LR, Jackson, AR, Bizon, C, Nelson, T, Powell, B, Freimuth, RR, Strande, N, Shah, N, Paithankar, S, Wright, MW, Dwight, S, Zhen, J, Landrum, M, McGarvey, P, Babb, L, Plon, SE, Milosavljevic, A, Clinical Genome (ClinGen) Resource, -

Hum. Mutat. 2018
12431996 Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein

Xia, Y, Pao, GM, Chen, HW, Verma, IM, Hunter, T

J. Biol. Chem. 2003
16489000 BRCA1 DNA-binding activity is stimulated by BARD1

Simons, AM, Horwitz, AA, Starita, LM, Griffin, K, Williams, RS, Glover, JN, Parvin, JD

Cancer Res. 2006
Participants
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Normal reaction
Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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