ClinVar Genomic variation as it relates to human health
NM_000465.4(BARD1):c.1933T>C (p.Cys645Arg)
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.1933T>C (p.Cys645Arg)
Variation ID: 142135 Accession: VCV000142135.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 214730479 (GRCh38) [ NCBI UCSC ] 2: 215595203 (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 Jul 8, 2016 Sep 29, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000465.4:c.1933T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000456.2:p.Cys645Arg missense NM_001282543.2:c.1876T>C NP_001269472.1:p.Cys626Arg missense NM_001282545.2:c.580T>C NP_001269474.1:p.Cys194Arg missense NM_001282548.2:c.523T>C NP_001269477.1:p.Cys175Arg missense NM_001282549.2:c.394T>C NP_001269478.1:p.Cys132Arg missense NR_104212.2:n.1898T>C non-coding transcript variant NR_104215.2:n.1841T>C non-coding transcript variant NR_104216.2:n.1097T>C non-coding transcript variant NC_000002.12:g.214730479A>G NC_000002.11:g.215595203A>G NG_012047.3:g.84233T>C LRG_297:g.84233T>C LRG_297t1:c.1933T>C LRG_297p1:p.Cys645Arg Q99728:p.Cys645Arg - Protein change
- C645R, C132R, C175R, C626R, C194R
- Other names
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NP_000456.2:p.Cys645Arg
- Canonical SPDI
- NC_000002.12:214730478:A:G
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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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0.02536 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00523
Exome Aggregation Consortium (ExAC) 0.00640
The Genome Aggregation Database (gnomAD) 0.02135
Trans-Omics for Precision Medicine (TOPMed) 0.02169
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02291
1000 Genomes Project 0.02536
1000 Genomes Project 30x 0.02608
- 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
Help
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 |
4170 | 4226 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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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Benign (2) |
criteria provided, multiple submitters, no conflicts
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Nov 25, 2014 | RCV000130983.8 | |
Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000411099.29 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000505902.12 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 7, 2016 | RCV000590690.9 | |
Benign (1) |
no assertion criteria provided
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- | RCV001354862.4 | |
Benign (1) |
criteria provided, single submitter
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Apr 19, 2022 | RCV002225437.3 |
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
Help
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
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000427206.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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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: SCV002505098.1
First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022 |
Number of individuals with the variant: 20
Geographic origin: South Africa
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Benign
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004016362.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Benign
(Aug 15, 2023)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760236.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Likely benign
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005258293.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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Benign
(Nov 18, 2014)
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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: SCV000292119.1
First in ClinVar: Jul 08, 2016 Last updated: Jul 08, 2016 |
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Benign
(Apr 07, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696762.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary:The c.1933T>C variant involves the alteration of a non-conserved nucleotide and causes change from medium size and polar (C) residue to large size and … (more)
Variant summary:The c.1933T>C variant involves the alteration of a non-conserved nucleotide and causes change from medium size and polar (C) residue to large size and basic. 4/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 1% (779/121331 chromosomes), predominantly observed in the African subpopulation at a frequency of 6.9% (720/10388 chromosomes) including 31 African homozygous occurrences. These frequencies exceed the maximal expected allele frequency for a pathogenic BARD1 variant of 0.0218%, suggesting this is a benign polymorphism found primarily in populations of African origin. One reputable clinical lab has classified this variant as benign (Ambry Genetics). It has previously been reported in patients with breast and ovarian cancer (Sauer 2005) without strong evidence for causality. Functional analyses showed this variant decreased the tumor suppression activity and apoptosis (Sauer 2005) and decreased the binding activity with poly(ADP-ribose) and BRCA1 (Li 2013). However, the in vivo implications of these functional findings have not been confirmed yet. Considering all, especially based on the high allele frequency in population cohorts, this variant is classified as Benign. (less)
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Benign
(Nov 22, 2016)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000806113.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Benign
(May 25, 2016)
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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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Counsyl
Accession: SCV000488640.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Benign
(Jul 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888803.3
First in ClinVar: Mar 17, 2018 Last updated: Dec 31, 2022 |
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Benign
(May 24, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809023.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Mar 03, 2015)
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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: SCV001939298.2
First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023 |
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Benign
(Feb 24, 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: SCV004019246.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more)
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Benign
(Feb 01, 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: SCV000557499.10
First in ClinVar: Jan 06, 2017 Last updated: Feb 20, 2024 |
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Benign
(Sep 22, 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:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157045.4
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
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Benign
(Nov 25, 2014)
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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: SCV000185900.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549576.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BARD1 p.Cys645Arg variant was identified in 1 of 504 proband chromosomes (frequency: 0.00198) from individuals or families with hereditary breast and ovarian cancer, and … (more)
The BARD1 p.Cys645Arg variant was identified in 1 of 504 proband chromosomes (frequency: 0.00198) from individuals or families with hereditary breast and ovarian cancer, and was also identified in 3 of 472 control chromosomes (frequency: 0.006) (De Brakeleer_2010_20077502, Sauer_2005_16061562). The variant was also identified in the following databases: dbSNP (ID: rs2228456) as “With Likely benign allele”, ClinVar (as likely benign by Illumina and benign by Ambry Genetics, Color Genomics, Counsyl, Invitae, and Quest Diagnostics), Clinvitae (3x), and Zhejiang Colon Cancer Database (3x). The variant was not identified in Cosmic, or MutDB databases. The variant was identified in control databases in 1841 of 277108 chromosomes (56 homozygous) at a frequency of 0.006644 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1657 (55 homozygous) of 24032 chromosomes (freq: 0.06895), “Other” in 23 (1 homozygous) of 6464 chromosomes (freq: 0.003558), Latino in 99 of 34416 chromosomes (freq: 0.002877), European (Non-Finnish) in 29 of 126612 chromosomes (freq: 0.000229), Ashkenazi Jewish in 14 of 10148 chromosomes (freq: 0.00138), European (Finnish) in 17 of 25784 chromosomes (freq: 0.000659), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), while the variant was not observed in the East Asian populations. Several functional studies identified the variant to be associated with breast and ovarian cancer, and may adversely affect the structure and function of the BRCT1 domain (Alshatwi_2012_23056176, Birrane_2007_17550235, Li_2013_23680151, Sauer_2005_16061562). The p.Cys645Arg residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (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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Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Deriving a mutation index of carcinogenicity using protein structure and protein interfaces. | Espinosa O | PloS one | 2014 | PMID: 24454733 |
Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. | Li M | Cancer cell | 2013 | PMID: 23680151 |
Identification of functional SNPs in BARD1 gene and in silico analysis of damaging SNPs: based on data procured from dbSNP database. | Alshatwi AA | PloS one | 2012 | PMID: 23056176 |
Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. | De Brakeleer S | Human mutation | 2010 | PMID: 20077502 |
Crystal structure of the BARD1 BRCT domains. | Birrane G | Biochemistry | 2007 | PMID: 17550235 |
Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer. | Sauer MK | Journal of medical genetics | 2005 | PMID: 16061562 |
Text-mined citations for rs2228456 ...
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.