VCV000418642.20 - ClinVar

NM_000465.4(BARD1):c.2251C>T (p.Arg751Trp)

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.

(7)

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.2251C>T (p.Arg751Trp)

Variation ID: 418642 Accession: VCV000418642.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 214728759 (GRCh38) [ NCBI UCSC ] 2: 215593483 (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	Apr 29, 2017	May 1, 2024	Dec 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000465.4:c.2251C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000456.2:p.Arg751Trp	missense
NM_001282543.2:c.2194C>T	NP_001269472.1:p.Arg732Trp	missense
NM_001282545.2:c.898C>T	NP_001269474.1:p.Arg300Trp	missense
NM_001282548.2:c.841C>T	NP_001269477.1:p.Arg281Trp	missense
NM_001282549.2:c.712C>T	NP_001269478.1:p.Arg238Trp	missense
NR_104212.2:n.2216C>T		non-coding transcript variant
NR_104215.2:n.2159C>T		non-coding transcript variant
NR_104216.2:n.1415C>T		non-coding transcript variant
NC_000002.12:g.214728759G>A
NC_000002.11:g.215593483G>A
NG_012047.3:g.85953C>T
LRG_297:g.85953C>T
LRG_297t1:c.2251C>T	LRG_297p1:p.Arg751Trp

... more HGVS ... less HGVS

Protein change

R751W, R732W, R238W, R281W, R300W

Other names

NP_000456.2:p.Arg751Trp

Canonical SPDI

NC_000002.12:214728758:G:A

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

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA2090056 dbSNP: rs139785364 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	4168	4224

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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Feb 24, 2017	RCV000484312.2
Hereditary cancer-predisposing syndrome	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jul 19, 2023	RCV000568699.10
Familial cancer of breast	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 26, 2023	RCV000817734.9
Hereditary breast ovarian cancer syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 19, 2022	RCV002225632.2

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 (Feb 24, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565855.4 First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017	Comment: This variant is denoted BARD1 c.2251C>T at the cDNA level, p.Arg751Trp (R751W) at the protein level, and results in the change of an Arginine to … (more) This variant is denoted BARD1 c.2251C>T at the cDNA level, p.Arg751Trp (R751W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Arg751Trp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Arg751Trp occurs at a position that is conserved through mammals and is located within the BRCT2 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BARD1 Arg751Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
Uncertain significance (Mar 17, 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: SCV000682765.3 First in ClinVar: Feb 19, 2018 Last updated: Jun 22, 2020
Uncertain significance (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State Accession: SCV002505089.1 First in ClinVar: Apr 29, 2022 Last updated: Apr 29, 2022	Number of individuals with the variant: 1 Geographic origin: South Africa
Uncertain significance (Dec 26, 2023)	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: SCV000958313.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 30441849‚ 34034685 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 751 of the BARD1 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 751 of the BARD1 protein (p.Arg751Trp). This variant is present in population databases (rs139785364, gnomAD 0.004%). This missense change has been observed in individual(s) with ovarian cancer and/or pancreatic cancer (PMID: 30441849, 34034685). ClinVar contains an entry for this variant (Variation ID: 418642). 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 (Jul 19, 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: SCV000660808.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 30441849‚ 33471991‚ 34034685 Comment: The p.R751W variant (also known as c.2251C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide … (more) The p.R751W variant (also known as c.2251C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide position 2251. The arginine at codon 751 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in a cohort of 333 Polish individuals diagnosed with ovarian cancer (Koczkowska M et al. Cancers (Basel), 2018 Nov;10:). This variant was also reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Additionally, this alteration was identified in an individual diagnosed with pancreatic cancer (Rapposelli IG et al. BMC Cancer, 2021 May;21:611). 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 (Nov 18, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529590.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The BARD1 c.2251C>T (p.R751W) missense variant has been reported in at least 2 individuals with pancreatic cancer and ovarian cancer (PMID: 34034685, 30441849). This variant … (more) The BARD1 c.2251C>T (p.R751W) missense variant has been reported in at least 2 individuals with pancreatic cancer and ovarian cancer (PMID: 34034685, 30441849). This variant is also reported in 2 women with breast cancer in a large dataset of 60,466 women with breast cancer, and 1/53,461 controls (PMID 33471991). This variant was observed in 2/24960 chromosomes in the African/African American population according to the Genome Aggregation Database (PMID: 32461654). This variant has been reported in ClinVar (Variation ID 418642). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (3) PubMed: 34034685‚ 30441849‚ 33471991
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004217201.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Comment:

This variant is denoted BARD1 c.2251C>T at the cDNA level, p.Arg751Trp (R751W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Arg751Trp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Arg751Trp occurs at a position that is conserved through mammals and is located within the BRCT2 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BARD1 Arg751Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 751 of the BARD1 protein (p.Arg751Trp). This variant is present in population databases (rs139785364, gnomAD 0.004%). This missense change has been observed in individual(s) with ovarian cancer and/or pancreatic cancer (PMID: 30441849, 34034685). ClinVar contains an entry for this variant (Variation ID: 418642). 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.R751W variant (also known as c.2251C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide position 2251. The arginine at codon 751 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in a cohort of 333 Polish individuals diagnosed with ovarian cancer (Koczkowska M et al. Cancers (Basel), 2018 Nov;10:). This variant was also reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Additionally, this alteration was identified in an individual diagnosed with pancreatic cancer (Rapposelli IG et al. BMC Cancer, 2021 May;21:611). 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.

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
Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer.	Rapposelli IG	BMC cancer	2021	PMID: 34034685
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
Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients.	Koczkowska M	Cancers	2018	PMID: 30441849

Text-mined citations for rs139785364 ...

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.2251C>T (p.Arg751Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139785364 ...