rs1057517589

Positions:

• chr2-214797098-GCT-G

Variant summary

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

The NM_000465.4(BARD1):​c.176_177del​(p.Glu59AlafsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000372 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BARD1 NM_000465.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.91

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-214797098-GCT-G is Pathogenic according to our data. Variant chr2-214797098-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371931.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.176_177del	p.Glu59AlafsTer8	frameshift_variant	2/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.176_177del	p.Glu59AlafsTer8	frameshift_variant	2/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152016 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: 0.00000342 AC: 5 AN: 1460692 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 726766

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Glu59Alafs*8) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 371931). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 23, 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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 23, 2022	ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2021	The c.176_177delAG pathogenic mutation, located in coding exon 2 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 176 to 177, causing a translational frameshift with a predicted alternate stop codon (p.E59Afs*8). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer and Ewing sarcoma (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22(11):1305-13; Venier RE et al. Pediatr Blood Cancer, 2019 09;66:e27824; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Rofes P et al. Genes (Basel), 2021 01;12:; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 25, 2022	This variant deletes 2 nucleotides in exon 2 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 with personal and/or family history of breast and/or ovarian cancer (PMID: 24549055, 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with breast or ovarian cancer (Castera et al., 2014; Lerner-Ellis et al., 2021; Rofes et al., 2021; Sandoval et al., 2021; Guindalini et al., 2022; Matta et al., 2022); This variant is associated with the following publications: (PMID: 24549055, 21344236, 20077502, 32708251, 36329109, 35264596, 32885271, 31157509, 33498765, 33606809) -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BARD1 p.Glu59AlafsX8 variant was identified in 1 of 1416 proband chromosomes (frequency: 0.0007) from individuals or families with hereditary breast and ovarian cancer (Castera 2014). The variant was also identified in ClinVar (as pathogenic by Invitae and likely pathogenic by Counsyl), and Clinvitae (2x). The variant was not identified in the dbSNP, Cosmic, MutDB, or Zhejiang Colon Cancer databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The c.176_177delAG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 59 and leads to a premature stop codon at position 66. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BARD1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1057517589; hg19: chr2-215661822;