ClinVar Genomic variation as it relates to human health
NM_000465.4(BARD1):c.1973G>A (p.Arg658His)
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.
Uncertain significance(4); Benign(1); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000465.4(BARD1):c.1973G>A (p.Arg658His)
Variation ID: 230212 Accession: VCV000230212.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 214730439 (GRCh38) [ NCBI UCSC ] 2: 215595163 (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 Dec 19, 2017 Oct 8, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000465.4:c.1973G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000456.2:p.Arg658His missense NM_001282543.2:c.1916G>A NP_001269472.1:p.Arg639His missense NM_001282545.2:c.620G>A NP_001269474.1:p.Arg207His missense NM_001282548.2:c.563G>A NP_001269477.1:p.Arg188His missense NM_001282549.2:c.434G>A NP_001269478.1:p.Arg145His missense NR_104212.2:n.1938G>A non-coding transcript variant NR_104215.2:n.1881G>A non-coding transcript variant NR_104216.2:n.1137G>A non-coding transcript variant NC_000002.12:g.214730439C>T NC_000002.11:g.215595163C>T NG_012047.3:g.84273G>A LRG_297:g.84273G>A LRG_297t1:c.1973G>A LRG_297p1:p.Arg658His - Protein change
- R658H, R639H, R145H, R188H, R207H
- Other names
- NP_000456.2:p.Arg658His
- Canonical SPDI
- NC_000002.12:214730438: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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0.00040 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 28, 2021 | RCV000223283.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000228912.14 | |
Likely benign (1) |
criteria provided, single submitter
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Jul 26, 2021 | RCV000430001.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 5, 2019 | RCV000589126.9 | |
Benign (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV002225516.2 | |
BARD1-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jan 30, 2024 | RCV003407748.6 |
Likely benign (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003491968.1 |
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
Help
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 benign
(Mar 14, 2018)
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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: SCV000688162.2
First in ClinVar: Feb 19, 2018 Last updated: May 19, 2019 |
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Uncertain significance
(Dec 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470363.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely benign
(Jul 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696764.2
First in ClinVar: Mar 17, 2018 Last updated: Aug 07, 2021 |
Comment:
Variant summary: BARD1 c.1973G>A (p.Arg658His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: BARD1 c.1973G>A (p.Arg658His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251370 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00025), suggesting that the variant is a benign polymorphism. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC) the variant was reported in 8/60466 cases, but was also found in 4/53461 controls (Dorling_2021 through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another missense variant affecting the same residues (c.1972C>T (p.Arg658Cys)) was classified as benign by our laboratory. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Sep 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000512249.4
First in ClinVar: Mar 08, 2017 Last updated: Dec 19, 2017 |
Comment:
Has not been previously published as pathogenic or benign to our knowledge
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Benign
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002505096.1
First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
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Uncertain significance
(Dec 28, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529561.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BARD1 c.1973G>A (p.R658H) variant has been reported in heterozygosity in at least eight individuals with breast cancer but was also observed in controls (PMID: … (more)
The BARD1 c.1973G>A (p.R658H) variant has been reported in heterozygosity in at least eight individuals with breast cancer but was also observed in controls (PMID: 33471991). It was observed in 11/35436 chromosomes, including 0 homozygotes, in the Latino subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 230212). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. There is no indication that this variant causes disease, but the evidence is insufficient currently to prove that conclusively. Thus, the clinical significance of this variant is currently uncertain. (less)
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Likely benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000837947.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 29, 2024)
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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: SCV000284936.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 658 of the BARD1 protein (p.Arg658His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 658 of the BARD1 protein (p.Arg658His). This variant is present in population databases (rs377227840, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer and/or uveal melanoma (PMID: 29769598, 35264596). ClinVar contains an entry for this variant (Variation ID: 230212). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Sep 19, 2018)
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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: SCV000273672.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Aug 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004234621.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 30, 2024)
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no assertion criteria provided
Method: clinical testing
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BARD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115628.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The BARD1 c.1973G>A variant is predicted to result in the amino acid substitution p.Arg658His. This variant has been reported in an individual with uveal melanoma … (more)
The BARD1 c.1973G>A variant is predicted to result in the amino acid substitution p.Arg658His. This variant has been reported in an individual with uveal melanoma that harbored variants in other genes (Table 1, Hajkova et al. 2018. PubMed ID: 29769598). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. It has conflicting interpretations of benign, likely benign, and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230212/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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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Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Germline mutation in the TP53 gene in uveal melanoma. | Hajkova N | Scientific reports | 2018 | PMID: 29769598 |
Text-mined citations for rs377227840 ...
HelpRecord last updated Oct 13, 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.