chr2-214780821-C-G

Position:

• chr2-214780821-C-G

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.1053G>C​(p.Thr351Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,613,832 control chromosomes in the GnomAD database, including 37,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3045 hom., cov: 32)
  • Exomes 𝑓: 0.22 (34886 hom.)
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.32

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-214780821-C-G is Benign according to our data. Variant chr2-214780821-C-G is described in ClinVar as [Benign]. Clinvar id is 142025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1053G>C	p.Thr351Thr	synonymous_variant	4/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1053G>C	p.Thr351Thr	synonymous_variant	4/11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29977 AN: 151940 Hom.: 3046 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.204

GnomAD3 exomes AF: 0.206 AC: 51790 AN: 251246 Hom.: 5547 AF XY: 0.209 AC XY: 28364 AN XY: 135784

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.216 AC: 316117 AN: 1461774 Hom.: 34886 Cov.: 37 AF XY: 0.217 AC XY: 157658 AN XY: 727180

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.245

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.197 AC: 29979 AN: 152058 Hom.: 3045 Cov.: 32 AF XY: 0.194 AC XY: 14407 AN XY: 74332

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.202

Alfa AF: 0.212 Hom.: 1121

Bravo AF: 0.201

Asia WGS AF: 0.194 AC: 675 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:5

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 24, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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. -

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	-0.79
CADD	Benign	0.17
DANN	Benign	0.30

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: rs2070096; hg19: chr2-215645545; COSMIC: COSV53608946; COSMIC: COSV53608946;