rs587782504

Positions:

• chr2-214730478-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000465.4(BARD1):​c.1932_1933del​(p.Cys645Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,874 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. V644V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BARD1 NM_000465.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PP5: Variant 2-214730478-CAT-C is Pathogenic according to our data. Variant chr2-214730478-CAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214730478-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.1932_1933del	p.Cys645Ter	frameshift_variant	10/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.1932_1933del	p.Cys645Ter	frameshift_variant	10/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461742 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727168

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: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 25, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Cys645*) 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). This variant is present in population databases (rs587782504, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with family history of breast cancer (PMID: 25452441, 26845104). ClinVar contains an entry for this variant (Variation ID: 142499). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2022	This variant deletes 2 nucleotides in exon 10 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. To our knowledge, this variant has been reported in individuals affected with breast and colorectal cancer in the literature (PMID: 25452441, 26845104, 29478780). This variant has been identified in 1/31408 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2014	​<span style="background-color: initial;">The c.1932_1933delAT pathogenic mutation, located in exon 10 of the BARD1 gene, results from a deletion of 2 nucleotides between positions 1932 and 1933, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -
Pathogenic, criteria provided, single submitter	research	Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	-	ACMG/AMP, PVS1, PM2, PP5 -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2018	This deletion of two nucleotides is denoted BARD1 c.1932_1933delAT at the cDNA level and p.Cys645Ter (C645X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGT[delAT]GTGA. The deletion creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BARD1 c.1932_1933delATAT has been reported in an individual with triple negative breast cancer and in an individual with a family history of breast cancer (Couch 2015, Shirts 2016). This variant is considered likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Sep 19, 2023	This variant has been identified by standard clinical testing. Selected ACMG criteria: Likely pathogenic (I):PM2;PVS1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 04, 2023	PVS1, PM2_SUP -

Malignant tumor of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 05, 2022

Variant summary: BARD1 c.1932_1933delAT (p.Cys645X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 6.6e-06 in 150904 control chromosomes (gnomAD v3.1.2). c.1932_1933delAT has been reported in the literature in individuals affected with breast cancer or colorectal cancer (Couch_2015, Shirt_2016, AlDubayan_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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: rs587782504; hg19: chr2-215595202;