Variant rs587781297 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_000465.4(BARD1):c.30_44delGCAGCCGAGGATCCG(p.Gln11_Arg15del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,589,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BARD1
NM_000465.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.91

Variant links:

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 links:

BARD1 (HGNC:):

BARD1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000465.4.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.30_44delGCAGCCGAGGATCCG	p.Gln11_Arg15del	disruptive_inframe_deletion	1/11	ENST00000260947.9	NP_000456.2	Q99728-1A0AVN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.30_44delGCAGCCGAGGATCCG	p.Gln11_Arg15del	disruptive_inframe_deletion	1/11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000490

AC:

AN:

203892

Hom.:

AF XY:

0.00

AC XY:

AN XY:

113130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000649

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1436882

Hom.:

AF XY:

0.00000841

AC XY:

AN XY:

713328

show subpopulations

Gnomad4 AFR exome

AF:

0.0000913

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000182

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000635

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2024	In-frame deletion of 5 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with biliary tract cancers but also in unaffected controls (PMID: 36243179); This variant is associated with the following publications: (PMID: 36243179) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2021	This variant causes an in-frame deletion of five amino acids of the BARD1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/203892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2023	The c.30_44del15 variant (also known as p.Q11_R15del) is located in coding exon 1 of the BARD1 gene. This variant results from an in-frame deletion of 15 nucleotides between nucleotide positions 30 and 44, resulting in a deletion of 5 amino acids. This amino acid region is poorly conserved in available vertebrate species. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This variant, c.30_44del, results in the deletion of 5 amino acid(s) of the BARD1 protein (p.Gln11_Arg15del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781297, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 419844). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over