ClinVar Genomic variation as it relates to human health
NM_000465.4(BARD1):c.946T>G (p.Leu316Val)
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.946T>G (p.Leu316Val)
Variation ID: 142233 Accession: VCV000142233.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 214780928 (GRCh38) [ NCBI UCSC ] 2: 215645652 (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 Oct 10, 2018 May 1, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000465.4:c.946T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000456.2:p.Leu316Val missense NM_001282543.2:c.889T>G NP_001269472.1:p.Leu297Val missense NM_001282545.2:c.215+16133T>G intron variant NM_001282548.2:c.159-28373T>G intron variant NM_001282549.2:c.364+11369T>G intron variant NR_104212.2:n.911T>G non-coding transcript variant NR_104215.2:n.854T>G non-coding transcript variant NC_000002.12:g.214780928A>C NC_000002.11:g.215645652A>C NG_012047.3:g.33784T>G LRG_297:g.33784T>G LRG_297t1:c.946T>G LRG_297p1:p.Leu316Val - Protein change
- L316V, L297V
- Other names
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- Canonical SPDI
- NC_000002.12:214780927:A:C
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3939 | 3993 |
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
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 14, 2023 | RCV000131232.14 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 19, 2024 | RCV000525698.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 22, 2022 | RCV001283885.5 |
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
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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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Uncertain significance
(Oct 29, 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: SCV002529664.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BARD1 c.946T>G (p.L316V) variant has been reported in at least one individual with advanced cancer (PMID: 28873162). It was observed in 6/24030 chromosomes of … (more)
The BARD1 c.946T>G (p.L316V) variant has been reported in at least one individual with advanced cancer (PMID: 28873162). It was observed in 6/24030 chromosomes of the African/African American 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 142233). In silico tools suggest the impact of the variant on protein function is benign though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jul 22, 2022)
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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: SCV002552596.2
First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with advanced cancer (Mandelker et al., 2017); This … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with advanced cancer (Mandelker et al., 2017); This variant is associated with the following publications: (PMID: 28873162) (less)
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Uncertain significance
(May 29, 2020)
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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: SCV001469366.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in a cohort of individuals undergoing an advanced cancer screening (PMID: 30422164 (2018)), and in a … (more)
In the published literature, this variant has been reported in a cohort of individuals undergoing an advanced cancer screening (PMID: 30422164 (2018)), and in a cohort of individuals with unspecified cancers (PMID: 28873162 (2017)). The frequency of this variant in the general population, 0.00024 (6/24916 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Nov 16, 2022)
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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: SCV000903903.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces leucine with valine at codon 316 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces leucine with valine at codon 316 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BARD1-related disorders in the literature but has been observed in an unaffected control individual (PMID: 26315354). This variant has been identified in 6/282234 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 19, 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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Invitae
Accession: SCV000633075.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 316 of the BARD1 protein (p.Leu316Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 316 of the BARD1 protein (p.Leu316Val). This variant is present in population databases (rs587782325, gnomAD 0.02%). This missense change has been observed in individual(s) with unspecified cancer and breast cancer (PMID: 28873162, 36315513). ClinVar contains an entry for this variant (Variation ID: 142233). 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 valine 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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Uncertain significance
(Apr 14, 2023)
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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: SCV000186187.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.L316V variant (also known as c.946T>G), located in coding exon 4 of the BARD1 gene, results from a T to G substitution at nucleotide … (more)
The p.L316V variant (also known as c.946T>G), located in coding exon 4 of the BARD1 gene, results from a T to G substitution at nucleotide position 946. The leucine at codon 316 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228986.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 01-13-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 01-13-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Myopia (present) , Abnormal erythrocyte morphology (present) , Obesity (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality … (more)
Myopia (present) , Abnormal erythrocyte morphology (present) , Obesity (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the female genitalia (present) , Abnormality of reproductive system physiology (present) , Anxiety (present) , Depression (present) (less)
Indication for testing: Presymptomatic, Family Testing
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-01-13
Testing laboratory interpretation: Uncertain significance
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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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Hereditary variants of unknown significance in African American women with breast cancer. | McDonald JT | PloS one | 2022 | PMID: 36315513 |
Missing Conflict of Interest Disclosure. | - | JAMA | 2018 | PMID: 30422164 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
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 |
Text-mined citations for rs587782325 ...
HelpRecord last updated May 08, 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.