rs750413473

Variant names:

• chr2-214728708-TCA-T
• rs750413473
• NM_000465.4:c.2300_2301delTG

Your query was ambiguous. Multiple possible variants found:

• chr2-214728708-TCA-T
• chr2-214728708-TCA-TCACA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PVS1_Moderate PP5_Very_Strong BS2

The NM_000465.4(BARD1):​c.2300_2301delTG​(p.Val767AspfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000235 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V767V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BARD1 NM_000465.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.12
• Publications: 10 publications found

Genes affected

BARD1 (HGNC:952): (BRCA1 associated RING domain 1) This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

BARD1 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0146 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 2-214728708-TCA-T is Pathogenic according to our data. Variant chr2-214728708-TCA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 230523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.2300_2301delTG	p.Val767AspfsTer4	frameshift_variant	Exon 11 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.2300_2301delTG	p.Val767AspfsTer4	frameshift_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251192 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461876 Hom.: 0 AF XY: 0.0000261 AC XY: 19 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1112006

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:6

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val767Aspfs*4) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the BARD1 protein. This variant is present in population databases (rs750413473, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 25452441, 26315354, 36551643). ClinVar contains an entry for this variant (Variation ID: 230523). This variant disrupts the C-terminal BRCT domain of BARD1 protein, which is required for chromosome stability and homology-directed repair (PMID: 17848578). A different variant (p.Val767fs) that lies downstream of this variant has been reported to affect BARD1 protein function (PMID: 30925164), this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2023

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant BARD1:c.2300_2301delTG, p.(Val767Aspfs*4), which is located in the coding exon 11 of the BARD1 gene, results from a deletion of nucleotide positions 2300 and 2301. This leads to a frameshift and a premature stop codon after four amino acids which is predicted to cause protein truncation. The variant affects the BRCT2 domain, which plays a crucial role in the protein function associated to in DNA repair and tumor suppression. The variant is described four times as pathogenic and five times as probably pathogenic in Clinvar (Clinvar ID: 230523). The varinat has been detected in individuals affected with breast cancer (PMID: 34445631, 32075053, 25452441) and ovarian carcinoma (PMID: 26315354). In a functional study, a loss of function of the truncated BARD1 gene product in relation to homology-directed repair was demonstrated based on a cell culture assay (PMID: 30925164). The variant is very rare, with an allele frequency in the overall population= 0.00001 (gnomAD V3.1.2). The variant is classified as Pathogenic. -

Feb 24, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Nov 09, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 09, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Sep 19, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 11, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2300_2301delTG variant, located in coding exon 11 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 2300 to 2301, causing a translational frameshift with a predicted alternate stop codon (p.V767Dfs*4). This alteration occurs at the 3' terminus of BARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last eleven amino acids of the protein. However, premature stop codons are typically deleterious in nature and structural analysis suggests this alteration would destabilize one of the BRCT domains in the BARD1 protein which are important for interactions with several proteins (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12; Feki A et al. Oncogene 2005 May; 24(23):3726-36; Edwards RA et al. Biochemistry 2008 Nov; 47(44):11446-56; Rodriguez M et al. J. Biol. Chem. 2003 Dec; 278(52):52914-8). This alteration was found to be non-functional in a homology-directed DNA repair (Adamovich AI et al. PLoS Genet. 2019 03;15:e1008049). This variant has been detected in at least two individuals with triple-negative breast cancer and one individual with serous ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb; 33(4):304-11; Gong Y et al. Int J Mol Sci. 2021 Aug;22:; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11)). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jan 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 11 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is not expected to trigger nonsense-mediated decay. This variant is predicted to delete or alter the last 11 amino acids of the BARD1 protein, including the C-terminus of the BRCT2 domain that facilitates protein-protein interaction involved in BARD1's role in DNA repair and tumor suppression (PMID: 17550235, 17848578, 26738429). A functional study has found the variant protein to be severely compromised for homology-directed repair activity in human cell assays (PMID: 30925164). This variant has been reported in three individuals affected with breast cancer, including two individuals with triple-negative breast cancer (PMID: 25452441, 34445631, 36551643). This variant has also been reported in an individual with ovarian cancer (PMID: 26315354) and in an individual over the age of 70 without cancer (FLOSSIES database). This variant has been identified in 9/282570 chromosomes 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 Likely Pathogenic. -

not provided Pathogenic:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation as the last 11 amino acids are lost and replaced with 3 incorrect amino acids in the critical BRCT 2 domain; Published functional studies suggest a damaging effect: reduced HDR activity (Adamovich et al., 2019); Observed in individuals with breast, ovarian, and other cancers (Couch et al., 2015; Ramus et al., 2015; Gong et al., 2021; Truong et al., 2021; El Jabbour et al., 2022; Nurmi et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25452441, 14578343, 26315354, 18842000, 17550235, 15782130, 29922827, 32075053, Imyanitov[case report], 30925164, 17848578, 34445631, 35078243, 36551643, 34654685) -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BARD1-related cancer predisposition Pathogenic:1

Jan 28, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750413473; hg19: chr2-215593432;