VCV000142117.27 - ClinVar

NM_000465.4(BARD1):c.2252G>A (p.Arg751Gln)

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.

(9)

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.2252G>A (p.Arg751Gln)

Variation ID: 142117 Accession: VCV000142117.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 214728758 (GRCh38) [ NCBI UCSC ] 2: 215593482 (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	Dec 6, 2016	Oct 8, 2024	Mar 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000465.4:c.2252G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000456.2:p.Arg751Gln	missense
NM_001282543.2:c.2195G>A	NP_001269472.1:p.Arg732Gln	missense
NM_001282545.2:c.899G>A	NP_001269474.1:p.Arg300Gln	missense
NM_001282548.2:c.842G>A	NP_001269477.1:p.Arg281Gln	missense
NM_001282549.2:c.713G>A	NP_001269478.1:p.Arg238Gln	missense
NR_104212.2:n.2217G>A		non-coding transcript variant
NR_104215.2:n.2160G>A		non-coding transcript variant
NR_104216.2:n.1416G>A		non-coding transcript variant
NC_000002.12:g.214728758C>T
NC_000002.11:g.215593482C>T
NG_012047.3:g.85954G>A
LRG_297:g.85954G>A
LRG_297t1:c.2252G>A	LRG_297p1:p.Arg751Gln

... more HGVS ... less HGVS

Protein change

R751Q, R732Q, R281Q, R300Q, R238Q

Other names

Canonical SPDI

NC_000002.12:214728757: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.

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA167450 dbSNP: rs587782246 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	Mar 22, 2023	RCV000130954.14
Familial cancer of breast	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV000233509.19
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 14, 2022	RCV000478725.6
Breast and/or ovarian cancer	Uncertain significance (1)	criteria provided, single submitter	Aug 29, 2022	RCV003492608.1
BARD1-related disorder	Uncertain significance (1)	no assertion criteria provided	May 16, 2024	RCV004739449.1

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 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 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565856.6 First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of sarcoma … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of sarcoma (Ballinger et al., 2016); This variant is associated with the following publications: (PMID: 24463508, 17550235, 27498913) (less)
Uncertain significance (Aug 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004240061.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Uncertain significance (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217190.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000427202.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Aug 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004234612.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Uncertain significance (Jan 16, 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: SCV000284949.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 27498913 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 751 of the BARD1 protein (p.Arg751Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 751 of the BARD1 protein (p.Arg751Gln). This variant is present in population databases (rs587782246, gnomAD 0.007%). This missense change has been observed in individual(s) with sarcoma (PMID: 27498913). ClinVar contains an entry for this variant (Variation ID: 142117). 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 (May 06, 2022)	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: SCV000688186.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 27498913 Comment: This missense variant replaces arginine with glutamine at codon 751 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with glutamine at codon 751 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 been reported in an individual affected with sarcoma (PMID: 27498913) This variant has been identified in 12/282618 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)
Uncertain significance (Mar 22, 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: SCV000185869.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 24463508‚ 25186627‚ 27498913 Comment: The p.R751Q variant (also known as c.2252G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide … (more) The p.R751Q variant (also known as c.2252G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide position 2252. The arginine at codon 751 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1 of 1162 patients with sarcoma (Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71). This alteration was also identified in two women from a breast cancer cohort (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (May 16, 2024)	no assertion criteria provided Method: clinical testing	BARD1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005355083.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BARD1 c.2252G>A variant is predicted to result in the amino acid substitution p.Arg751Gln. This variant has been reported as a variant of uncertain significance … (more) The BARD1 c.2252G>A variant is predicted to result in the amino acid substitution p.Arg751Gln. This variant has been reported as a variant of uncertain significance in one patient with synovial sarcoma (Ballinger et al. 2016. PubMed ID: 27498913), in two patients with breast cancer (Tung et al. 2014. PubMed ID: 25186627), and in one patient with biliary tract cancer (Okawa et al. 2023. PubMed ID: 36243179). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142117/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of sarcoma (Ballinger et al., 2016); This variant is associated with the following publications: (PMID: 24463508, 17550235, 27498913)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 751 of the BARD1 protein (p.Arg751Gln). This variant is present in population databases (rs587782246, gnomAD 0.007%). This missense change has been observed in individual(s) with sarcoma (PMID: 27498913). ClinVar contains an entry for this variant (Variation ID: 142117). 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:

This missense variant replaces arginine with glutamine at codon 751 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 been reported in an individual affected with sarcoma (PMID: 27498913) This variant has been identified in 12/282618 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.

Comment:

The p.R751Q variant (also known as c.2252G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide position 2252. The arginine at codon 751 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1 of 1162 patients with sarcoma (Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71). This alteration was also identified in two women from a breast cancer cohort (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

The BARD1 c.2252G>A variant is predicted to result in the amino acid substitution p.Arg751Gln. This variant has been reported as a variant of uncertain significance in one patient with synovial sarcoma (Ballinger et al. 2016. PubMed ID: 27498913), in two patients with breast cancer (Tung et al. 2014. PubMed ID: 25186627), and in one patient with biliary tract cancer (Okawa et al. 2023. PubMed ID: 36243179). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142117/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Monogenic and polygenic determinants of sarcoma risk: an international genetic study.	Ballinger ML	The Lancet. Oncology	2016	PMID: 27498913
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.	Tung N	Cancer	2015	PMID: 25186627
A polygenic burden of rare disruptive mutations in schizophrenia.	Purcell SM	Nature	2014	PMID: 24463508

Text-mined citations for rs587782246 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000465.4(BARD1):c.2252G>A (p.Arg751Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587782246 ...