rs1553612222

Positions:

• chr2-214728967-TCCCCA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000465.4(BARD1):​c.2038_2042delTGGGG​(p.Trp680fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BARD1 NM_000465.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.54

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 14 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 0.127 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-214728967-TCCCCA-T is Pathogenic according to our data. Variant chr2-214728967-TCCCCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 530079.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.2038_2042delTGGGG	p.Trp680fs	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.2038_2042delTGGGG	p.Trp680fs	frameshift_variant	11/11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 25, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2017	This sequence change results in a premature translational stop signal in the BARD1 gene (p.Trp680Asnfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acids of the BARD1 protein. This variant is not present in population databases (ExAC no frequency). 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. This truncating change removes most of the BRCT2 domain of BARD1 (residues 666-777) (PMID: 26315354, 17550235). While the functional significance of deleting the second BRCT domain has not been addressed experimentally, studies suggest that both BRCT repeats in BARD1 are necessary for its normal functioning (PMID: 17550235, 26738429, 17848578). This variant has not been reported in the literature in individuals with BARD1-related disease. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2020

The c.2038_2042delTGGGG variant, located in coding exon 11 of the BARD1 gene, results from a deletion of 5 nucleotides at nucleotide positions 2038 to 2042, causing a translational frameshift with a predicted alternate stop codon (p.W680Nfs*12). This alteration occurs at the 3' terminus of theBARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 87 amino acids of the protein. However, structural analysis suggests this alteration results in loss of a large part of a well-ordered C-terminal BRCT domain, which could disrupt protein-protein interactions (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; Ambry internal data). In addition, the BARD1 C-terminal BRCT domain has been implicated in chromosomal stability and homology-directed repair function (Laufer M et al. J. Biol. Chem., 2007 Nov;282:34325-33). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553612222; hg19: chr2-215593691;