ClinVar Genomic variation as it relates to human health
NM_000465.4(BARD1):c.2267G>A (p.Trp756Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000465.4(BARD1):c.2267G>A (p.Trp756Ter)
Variation ID: 863791 Accession: VCV000863791.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 214728743 (GRCh38) [ NCBI UCSC ] 2: 215593467 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 15, 2020 May 1, 2024 May 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000465.4:c.2267G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000456.2:p.Trp756Ter nonsense NM_000465.2:c.2267G>A NM_001282543.2:c.2210G>A NP_001269472.1:p.Trp737Ter nonsense NM_001282545.2:c.914G>A NP_001269474.1:p.Trp305Ter nonsense NM_001282548.2:c.857G>A NP_001269477.1:p.Trp286Ter nonsense NM_001282549.2:c.728G>A NP_001269478.1:p.Trp243Ter nonsense NR_104212.2:n.2232G>A non-coding transcript variant NR_104215.2:n.2175G>A non-coding transcript variant NR_104216.2:n.1431G>A non-coding transcript variant NC_000002.12:g.214728743C>T NC_000002.11:g.215593467C>T NG_012047.3:g.85969G>A LRG_297:g.85969G>A LRG_297t1:c.2267G>A LRG_297p1:p.Trp756Ter - Protein change
- W286*, W305*, W737*, W243*, W756*
- Other names
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- Canonical SPDI
- NC_000002.12:214728742:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BARD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4007 | 4063 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 25, 2023 | RCV001070842.10 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2020 | RCV001179860.6 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(May 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001344649.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This variant changes 1 nucleotide in exon 11 of the BARD1 gene, creating a premature translation stop signal. While this variant is not expected to … (more)
This variant changes 1 nucleotide in exon 11 of the BARD1 gene, creating a premature translation stop signal. While this variant is not expected to trigger nonsense-mediated decay, this variant is predicted to partially truncate the BRCT domain that facilitates protein-protein interaction involved in BARD1's role in DNA repair and tumor suppression (PMID: 17550235, 17848578, 26738429). This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(May 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004043502.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Apr 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001236116.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD … (more)
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 863791). This variant disrupts a region of the BARD1 protein in which other variant(s) (p.Val767Aspfs*4) have been determined to be pathogenic (PMID: 17848578, 25452441, 26315354, 30925164). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Trp756*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the BARD1 protein. (less)
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002737941.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W756* variant (also known as c.2267G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide … (more)
The p.W756* variant (also known as c.2267G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide position 2267. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BARD1, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 22 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests this alteration results in loss of a large part of a well-ordered C-terminal BRCT domain with destabilization of the structure, which could disrupt protein-protein interactions (Birrane G et al. Biochemistry. 2007 Jul; 46(26):7706-12; Feki A et al. Oncogene. 2005 May; 24(23):3726-36; Edwards RA et al. Biochemistry. 2008 Nov; 47(44):11446-56; Rodriguez M et al. J. Biol. Chem. 2003 Dec; 278(52):52914-8; Ambry internal data). In addition, this alteration impacts the BRCT domain of BARD1, which has been shown to be necessary for homology-directed DNA repair (Laufer M et al. J Biol Chem, 2007 Nov;282:34325-33, Adamovich AI et al. PLoS Genet, 2019 03;15:e1008049). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity. | Adamovich AI | PLoS genetics | 2019 | PMID: 30925164 |
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. | Couch FJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25452441 |
The BARD1 C-terminal domain structure and interactions with polyadenylation factor CstF-50. | Edwards RA | Biochemistry | 2008 | PMID: 18842000 |
Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair. | Laufer M | The Journal of biological chemistry | 2007 | PMID: 17848578 |
Crystal structure of the BARD1 BRCT domains. | Birrane G | Biochemistry | 2007 | PMID: 17550235 |
BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. | Feki A | Oncogene | 2005 | PMID: 15782130 |
Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. | Rodriguez M | The Journal of biological chemistry | 2003 | PMID: 14578343 |
Text-mined citations for rs1358155595 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.