VCV000926715.11 - ClinVar

NM_000465.4(BARD1):c.157del (p.Cys53fs)

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.

(4)

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.

Pathogenic

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.157del (p.Cys53fs)

Variation ID: 926715 Accession: VCV000926715.11

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2q35 2: 214809413 (GRCh38) [ NCBI UCSC ] 2: 215674137 (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	Jun 22, 2020	May 1, 2024	May 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000465.4:c.157del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000456.2:p.Cys53fs	frameshift
NM_000465.2:c.157delT
NM_001282543.2:c.157del	NP_001269472.1:p.Cys53fs	frameshift
NM_001282545.2:c.157del	NP_001269474.1:p.Cys53fs	frameshift
NM_001282548.2:c.157del	NP_001269477.1:p.Cys53fs	frameshift
NM_001282549.2:c.157del	NP_001269478.1:p.Cys53fs	frameshift
NR_104212.2:n.271del		non-coding transcript variant
NR_104215.2:n.271del		non-coding transcript variant
NR_104216.2:n.271del		non-coding transcript variant
NC_000002.12:g.214809414del
NC_000002.11:g.215674138del
NG_012047.3:g.5299del
LRG_297:g.5299del
LRG_297t1:c.157del	LRG_297p1:p.Cys53fs

... more HGVS ... less HGVS

Protein change

C53fs

Other names

Canonical SPDI

NC_000002.12:214809412:AA: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.

Links

dbSNP: rs1696452439 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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 20, 2021	RCV001189519.6
Familial cancer of breast	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 18, 2023	RCV001862998.7

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.
Pathogenic (Jul 28, 2021)	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: SCV001356828.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 08, 2022	Comment: This variant deletes 1 nucleotides in exon 1 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 1 nucleotides in exon 1 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 33498765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (May 18, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004045067.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Oct 24, 2022)	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: SCV002234799.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 33498765‚ 20077502‚ 21344236 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 926715). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 926715). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 33498765). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys53Valfs*5) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). (less)
Pathogenic (Oct 20, 2021)	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: SCV002709506.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 33498765 Comment: The c.157delT pathogenic mutation, located in coding exon 1 of the BARD1 gene, results from a deletion of one nucleotide at nucleotide position 157, causing … (more) The c.157delT pathogenic mutation, located in coding exon 1 of the BARD1 gene, results from a deletion of one nucleotide at nucleotide position 157, causing a translational frameshift with a predicted alternate stop codon (p.C53Vfs*5). This alteration was detected in two unrelated individuals in a cohort of 4015 Spanish individuals with a personal and/or family history of breast or ovarian cancer who underwent multi-gene panel testing (Rofes P et al. Genes (Basel), 2021 01;12:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

This variant deletes 1 nucleotides in exon 1 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 33498765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 926715). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 33498765). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys53Valfs*5) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236).

Comment:

The c.157delT pathogenic mutation, located in coding exon 1 of the BARD1 gene, results from a deletion of one nucleotide at nucleotide position 157, causing a translational frameshift with a predicted alternate stop codon (p.C53Vfs*5). This alteration was detected in two unrelated individuals in a cohort of 4015 Spanish individuals with a personal and/or family history of breast or ovarian cancer who underwent multi-gene panel testing (Rofes P et al. Genes (Basel), 2021 01;12:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
BARD1 Pathogenic Variants are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort.	Rofes P	Genes	2021	PMID: 33498765
Cancer predisposing BARD1 mutations in breast-ovarian cancer families.	Ratajska M	Breast cancer research and treatment	2012	PMID: 21344236
Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families.	De Brakeleer S	Human mutation	2010	PMID: 20077502

Text-mined citations for rs1696452439 ...

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.157del (p.Cys53fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1696452439 ...