VCV000482769.20 - ClinVar

NM_000465.4(BARD1):c.1906G>A (p.Val636Ile)

Germline

Classification

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000465.4(BARD1):c.1906G>A (p.Val636Ile)

Variation ID: 482769 Accession: VCV000482769.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 214730506 (GRCh38) [ NCBI UCSC ] 2: 215595230 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jan 1, 2018	May 1, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000465.4:c.1906G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000456.2:p.Val636Ile	missense
NM_001282543.2:c.1849G>A	NP_001269472.1:p.Val617Ile	missense
NM_001282545.2:c.553G>A	NP_001269474.1:p.Val185Ile	missense
NM_001282548.2:c.496G>A	NP_001269477.1:p.Val166Ile	missense
NM_001282549.2:c.367G>A	NP_001269478.1:p.Val123Ile	missense
NR_104212.2:n.1871G>A		non-coding transcript variant
NR_104215.2:n.1814G>A		non-coding transcript variant
NR_104216.2:n.1070G>A		non-coding transcript variant
NC_000002.12:g.214730506C>T
NC_000002.11:g.215595230C>T
NG_012047.3:g.84206G>A
LRG_297:g.84206G>A
LRG_297t1:c.1906G>A	LRG_297p1:p.Val636Ile

... more HGVS ... less HGVS

Protein change

V636I, V166I, V185I, V123I, V617I

Other names

Canonical SPDI

NC_000002.12:214730505:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA350451343 dbSNP: rs1553612541 VarSome

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
Gene	OMIM	HI score Help 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.
BARD1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4007	4063

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jun 14, 2023	RCV000567084.9
Familial cancer of breast	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000688096.13

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.
Uncertain significance (Nov 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001347609.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022	Comment: This missense variant replaces valine with isoleucine at codon 636 of the BARD1 protein. Computational prediction tool suggests that this variant may not impact protein … (more) This missense variant replaces valine with isoleucine at codon 636 of the BARD1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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)
Uncertain significance (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000837950.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Uncertain significance (Jun 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217259.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000815695.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 35264596 Comment: This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 636 of the BARD1 protein (p.Val636Ile). … (more) This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 636 of the BARD1 protein (p.Val636Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 482769). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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)
Uncertain significance (Jun 14, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000668187.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 35264596 Comment: The p.V636I variant (also known as c.1906G>A), located in coding exon 10 of the BARD1 gene, results from a G to A substitution at nucleotide … (more) The p.V636I variant (also known as c.1906G>A), located in coding exon 10 of the BARD1 gene, results from a G to A substitution at nucleotide position 1906. The valine at codon 636 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly 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)

Comment:

This missense variant replaces valine with isoleucine at codon 636 of the BARD1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 636 of the BARD1 protein (p.Val636Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 482769). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

Comment:

The p.V636I variant (also known as c.1906G>A), located in coding exon 10 of the BARD1 gene, results from a G to A substitution at nucleotide position 1906. The valine at codon 636 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly 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.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Detection of germline variants in Brazilian breast cancer patients using multigene panel testing.	Guindalini RSC	Scientific reports	2022	PMID: 35264596

Text-mined citations for rs1553612541 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000465.4(BARD1):c.1906G>A (p.Val636Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1553612541 ...