chr2-214728708-TCA-T

Position:

• chr2-214728708-TCA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000465.4(BARD1):​c.2300_2301delTG​(p.Val767fs) 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 (★★).

• 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:12
• Conservation: PhyloP100: 7.12

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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 0 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 [Likely_pathogenic]. Clinvar id is 230523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.2300_2301delTG	p.Val767fs	frameshift_variant	11/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.2300_2301delTG	p.Val767fs	frameshift_variant	11/11	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

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251192 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135752

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000828

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Aug 22, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	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). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 09, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	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. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 19, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2023	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. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs750413473; hg19: chr2-215593432;