rs2070093

chr2-214767532-A-Gchr2-214767532-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000465.4(BARD1):c.1518T>C(p.His506=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,612,710 control chromosomes in the GnomAD database, including 522,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44244 hom., cov: 32)
  • Exomes 𝑓: 0.81 (478353 hom.)
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.241

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-214767532-A-G is Benign according to our data. Variant chr2-214767532-A-G is described in ClinVar as [Benign]. Clinvar id is 183704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.241 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.1518T>C	p.His506=	synonymous_variant	6/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.1518T>C	p.His506=	synonymous_variant	6/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114859 AN: 151980 Hom.: 44222 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.737

GnomAD3 exomes AF: 0.817 AC: 205304 AN: 251312 Hom.: 84649 AF XY: 0.819 AC XY: 111212 AN XY: 135820

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.816

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.954

Gnomad SAS exome AF: 0.841

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.806

Gnomad OTH exome AF: 0.793

GnomAD4 exome AF: 0.808 AC: 1179667 AN: 1460612 Hom.: 478353 Cov.: 54 AF XY: 0.810 AC XY: 588295 AN XY: 726672

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.808

Gnomad4 ASJ exome AF: 0.824

Gnomad4 EAS exome AF: 0.940

Gnomad4 SAS exome AF: 0.841

Gnomad4 FIN exome AF: 0.891

Gnomad4 NFE exome AF: 0.804

Gnomad4 OTH exome AF: 0.791

GnomAD4 genome AF: 0.756 AC: 114924 AN: 152098 Hom.: 44244 Cov.: 32 AF XY: 0.761 AC XY: 56575 AN XY: 74340

Gnomad4 AFR AF: 0.599

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.829

Gnomad4 EAS AF: 0.949

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.899

Gnomad4 NFE AF: 0.805

Gnomad4 OTH AF: 0.740

Alfa AF: 0.780 Hom.: 23967

Bravo AF: 0.738

Asia WGS AF: 0.861 AC: 2994 AN: 3478

EpiCase AF: 0.793

EpiControl AF: 0.795

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.0
Dann	Benign	0.41

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: rs2070093; hg19: chr2-215632256; COSMIC: COSV53617490;