GeneBe

BARD1

protein-coding

BRCA1 associated RING domain 1, the group of Ankyrin repeat domain containing|Ring finger proteins|BRCA1 B complex

Gene summary

This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

MANE transcript

NM_000465.4

Inheritance

AD

ClinVar variants

P:694U:2068B:1149

Top phenotype

Breast cancer, susceptibility to

gnomAD constraint

pLI —, LoF o/e 1.03

Max pathogenic AF

—

Genomic locus

chr2:214,725,646-214,809,683

External References & Databases

Ensembl (ENSG00000138376)NCBI Gene (580)OMIM (601593)HGNC:952GenCCUniProt (Q99728)AlphaFoldClinVar (BARD1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~84.0 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

BARD1-related cancer predispositionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700267

Submitter: ClinGen

BARD1 was discovered as a binding partner to BRCA1 in 1996 (Wu et al., PMID: 8944023) and was first reported in relation to hereditary breast cancer in 1998 (Thai et al., PMID: 9425226). BARD1-related cancer predisposition is characterized by a susceptibility to breast cancer with emerging evidence suggesting the association of other cancer types including neuroblastoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern. Therefore, breast cancer and neuroblastoma have been lumped into this curation. Please note, autosomal dominant familial ovarian cancer (MONDO:0016248) has been curated separately due to conflicting evidence. The mechanism of pathogenicity is loss of function in which BRCA1 binding is disrupted and subsequent loss of DNA damage response. 6 predicted null variants (nonsense and frameshift) and 2 missense variants reported in 8 probands with breast cancer in 5 publications (PMIDs: 2550351, 31371347, 21344236, 23334666, 28726808) are included in this curation. Several case-control studies further support the association of breast cancer (PMIDs: 15342711, 28418444, 28649662, 31036035, 33471991, 35172496). Additionally, a case-control study supports the association of neuroblastoma (PMIDs: 37688579, 37688570, 36747619). More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. This gene-disease relationship is also supported by experimental evidence, including in vitro functional assays and animal models (2.5 Points, PMIDs: 18443292, 30925164, 33623049). Cells models with BARD1 variants showed impaired DNA damage in line with the proposed mechanism. In addition, both mammary gland conditional knockout Bard1 mice and a BARD1 variant xenograft model showed development of a breast cancer-like mammary tumor. In summary, there is definitive evidence supporting the relationship between BARD1 and autosomal dominant inherited BARD1-related cancer predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as definitive for hereditary breast cancer (MONDO:0016419) by the Breast/Ovarian Cancer GCEP on 08/09/2017. This re-curation as definitive was approved by the ClinGen Hereditary Cancer GCEP on 01/26/2024 (SOP Version 10).

hereditary breast carcinomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Ambry Genetics

hereditary breast carcinomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Labcorp Genetics (formerly Invitae)

familial ovarian cancerNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0016248

Submitter: ClinGen

BARD1 was first reported in relation to Ovarian Cancer in 1998 (Thai et al., PMID: 9425226). BARD1 was proposed to be linked to ovarian cancer due to its relationship with breast cancer and an early case-control study (PMID: 26720728). The mechanism of pathogenicity was proposed to be via BRCA1 binding and subsequent loss of DNA damage response. BARD1-related cancer predisposition MONDO:0700267 is characterized by a susceptibility to breast cancer with emerging evidence suggesting the association of other cancer types including neuroblastoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we did a split curation for BARD1-related ovarian cancer predisposition given evidence to dispute or refute. The prior curation in 2017 was Limited. For ovarian cancer, 1 variant has been reported in 1 proband in 1 study (PMID: 9425226), no other clear disease causing variants could be identified. This gene-disease relationship has been studied in at least 8 case-control studies at the aggregate variant level and 1 case-control study (PMID:15342711) at the single variant level. Of these studies, one study reports an association (PMID: 26720728) while 4 report no association (non-significant Odds Ratio), and another 3 reported that despite evaluating BARD1, no associated variants were identified in any cases (PMIDs: 31036035, 15342711, 29020732). In summary, the evidence supporting the relationship between BARD1 and autosomal dominant hereditary ovarian cancer has been disputed and no valid evidence remains to support the claim. More evidence is needed to entirely refute the role BARD1 plays in this disease. This re-curation as disputed was approved by the ClinGen Hereditary Cancer GCEP on 04/26/2024 (SOP Version 10). As a result of this re-evaluation, the overall classification changed from Limited to Disputed.

breast cancerDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: G2P

Clinical Genomic Database (CGD)

Breast cancer, susceptibility toAD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Though the availability of empirical data is incomplete as applies to both screening strategies and prophylactic treatment, surveillance may allow early detection and management of cancer

Refs: 14550946; 16768547; 16825437; 17333333; 24549055; 25058500Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BARD1 variants in ClinVar

29 Conditions Cataloged
Familial cancer of breastTotal: 3527
Hereditary cancer-predisposing syndromeTotal: 3030
not providedTotal: 753
not specifiedTotal: 411
BARD1-related cancer predispositionTotal: 109
Hereditary breast ovarian cancer syndromeTotal: 98
BARD1-related disorderTotal: 87
Malignant tumor of breastTotal: 75

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000465.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
1
clinvar
9
clinvar
806
clinvar
84
clinvar
 903
missense
14
clinvar
15
clinvar
2029
clinvar
252
clinvar
6
clinvar
 2316
nonsense
110
clinvar
57
clinvar
4
clinvar
 171
start loss
1
clinvar
3
clinvar
 4
frameshift
287
clinvar
107
clinvar
12
clinvar
 406
splice donor/acceptor (+/-2bp)
5
clinvar
94
clinvar
11
clinvar
1
clinvar
 111
Total41927520681059903911

Highest pathogenic variant AF is 0.0002544878

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000465.4RefSeqNP_000456.211MANE Select
ENST00000260947.9EnsemblENSP00000260947.411MANE Select
NM_001282543.2RefSeqNP_001269472.110Standard
NM_001282545.2RefSeqNP_001269474.17Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Homologous recombination - Homo sapiens (human)
  • Integrated Breast Cancer Pathway
  • Retinoblastoma (RB) in Cancer
  • HDR through Single Strand Annealing (SSA)
  • HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)

Biological Process

  • DNA double-strand break processing
  • tissue homeostasis
  • DNA replication
  • double-strand break repair via nonhomologous end joining
  • cellular response to DNA damage stimulus

Molecular Function

  • RNA binding
  • ubiquitin-protein transferase activity
  • protein binding
  • kinase binding
  • protein homodimerization activity

Cellular Component

  • ubiquitin ligase complex
  • nucleus
  • nucleoplasm
  • cytoplasm
  • nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000260947
Coding exons
11
Length
84059
Individuals with no LoFs
125673
Homozygous LoFs
0
Heterozygous LoFs
75
Defined
125748
p
0.000298
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.5484474161.080.00002065097
Missense (PolyPhen)103121.320.849011463
Synonymous-1.121721541.110.000007871472
Loss of Function-0.1533635.01.030.00000180451

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000270.00026rare
Ashkenazi Jewish00.0absent
East Asian0.000550.00054rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000400.00040rare
South Asian0.000200.00020rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage. {ECO:0000269|PubMed:12890688, ECO:0000269|PubMed:14976165, ECO:0000269|PubMed:20351172}.;

Recessive Scores

pRec
0.282

Intolerance Scores

LoFtool
0.859
RVIS EVS
0.94
RVIS percentile EVS
89.86

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.582

Gene Damage Prediction

AllRecessiveDominant
MendelianHighMediumHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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