2-214767531-C-T

Position:

chr2-214767531-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000465.4(BARD1):c.1519G>A(p.Val507Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,612,252 control chromosomes in the GnomAD database, including 109,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10608 hom., cov: 32)

Exomes 𝑓: 0.37 ( 99049 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -5.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3202429E-4).

BP6

Variant 2-214767531-C-T is Benign according to our data. Variant chr2-214767531-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 140757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.1519G>A	p.Val507Met	missense_variant	6/11	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.1519G>A	p.Val507Met	missense_variant	6/11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

56406

AN:

151950

Hom.:

10590

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.417

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.412

Gnomad FIN

AF:

0.467

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.379

GnomAD3 exomes

AF:

0.374

AC:

93956

AN:

251276

Hom.:

17978

AF XY:

0.376

AC XY:

51102

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.375

Gnomad AMR exome

AF:

0.294

Gnomad ASJ exome

AF:

0.416

Gnomad EAS exome

AF:

0.366

Gnomad SAS exome

AF:

0.403

Gnomad FIN exome

AF:

0.468

Gnomad NFE exome

AF:

0.371

Gnomad OTH exome

AF:

0.355

GnomAD4 exome

AF:

0.366

AC:

535041

AN:

1460184

Hom.:

99049

Cov.:

AF XY:

0.368

AC XY:

267556

AN XY:

726492

show subpopulations

Gnomad4 AFR exome

AF:

0.367

Gnomad4 AMR exome

AF:

0.298

Gnomad4 ASJ exome

AF:

0.406

Gnomad4 EAS exome

AF:

0.358

Gnomad4 SAS exome

AF:

0.407

Gnomad4 FIN exome

AF:

0.472

Gnomad4 NFE exome

AF:

0.360

Gnomad4 OTH exome

AF:

0.365

GnomAD4 genome

AF:

0.371

AC:

56462

AN:

152068

Hom.:

10608

Cov.:

AF XY:

0.376

AC XY:

27971

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.371

Gnomad4 AMR

AF:

0.319

Gnomad4 ASJ

AF:

0.417

Gnomad4 EAS

AF:

0.372

Gnomad4 SAS

AF:

0.412

Gnomad4 FIN

AF:

0.467

Gnomad4 NFE

AF:

0.364

Gnomad4 OTH

AF:

0.379

Alfa

AF:

0.357

Hom.:

16290

Bravo

AF:

0.354

ESP6500AA

AF:

0.290

AC:

1278

ESP6500EA

AF:

0.276

AC:

2372

ExAC

AF:

0.378

AC:

45922

Asia WGS

AF:

0.378

AC:

1313

AN:

3478

EpiCase

AF:

0.357

EpiControl

AF:

0.354

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 25, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25785002, 27153395, 26350354, 14550946, 19412175, 9425226, 23222812) -

Hereditary cancer-predisposing syndrome

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0080

DANN

Benign

0.66

DEOGEN2

Benign

0.064

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.00013

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.11

Sift

Benign

0.27

T;.

Sift4G

Uncertain

0.039

D;D

Polyphen

0.058

B;.

Vest4

0.026

MPC

0.077

ClinPred

0.024

GERP RS

-11

Varity_R

0.11

gMVP

0.12

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

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