2-214730416-G-A

Position:

• chr2-214730416-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000465.4(BARD1):​c.1996C>T​(p.Gln666Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000616 in 1,460,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BARD1 NM_000465.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.94

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 12 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. Fraction of 0.145 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 2-214730416-G-A is Pathogenic according to our data. Variant chr2-214730416-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182051.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.1996C>T	p.Gln666Ter	stop_gained	10/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1996C>T	p.Gln666Ter	stop_gained	10/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460472 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726582

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

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	Jan 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 26, 2023	This sequence change creates a premature translational stop signal (p.Gln666*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 112 amino acid(s) of the BARD1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of BARD1-related conditions (PMID: 26315354, 26681312). ClinVar contains an entry for this variant (Variation ID: 182051). 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. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2024	Nonsense variant predicted to result in protein truncation, as the last 112 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal and family history of breast and other cancers (PMID: 34326862, 26681312, 25186627, 30130155); This variant is associated with the following publications: (PMID: 28281021, 26315354, 26681312, 25186627, 30733081, 34404389, 17550235, 30925164, 17848578, 15040442, 29292755, 33610559, 30130155, 34326862) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This variant changes 1 nucleotide in exon 10 of the BARD1 gene, creating a premature translation stop signal at codon 666. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as truncated protein lacking the functional BRCT2 domain (a.a. 667-777) that is critical for BARD1 protein function (PMID: 17848578, 30925164). This variant has been observed in individuals affected with breast cancer, including one individuals diagnosed before age 50 (PMID: 25186627, 26681312). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 10, 2022	The p.Q666* pathogenic mutation (also known as c.1996C>T), located in coding exon 10 of the BARD1 gene, results from a C to T substitution at nucleotide position 1996. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration occurs at the 3' terminus of theBARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 112 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration was previously identified in a patient with breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D;N
Vest4		0.94
ClinPred		1.0	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs730881422; hg19: chr2-215595140;