2-214780740-C-G

Variant names:

Variant summary

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

The NM_000465.4(BARD1):c.1134G>C(p.Arg378Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,613,584 control chromosomes in the GnomAD database, including 277,240 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 Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 22198 hom., cov: 31)

Exomes 𝑓: 0.59 ( 255042 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.395

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:

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=5.4821157E-6).

BP6

Variant 2-214780740-C-G is Benign according to our data. Variant chr2-214780740-C-G is described in ClinVar as [Benign]. Clinvar id is 142769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.1134G>C	p.Arg378Ser	missense_variant	Exon 4 of 11	ENST00000260947.9	NP_000456.2	Q99728-1A0AVN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9 link	c.1134G>C	p.Arg378Ser	missense_variant	Exon 4 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.530

AC:

80463

AN:

151750

Hom.:

22188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.562

Gnomad AMR

AF:

0.470

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.373

Gnomad SAS

AF:

0.482

Gnomad FIN

AF:

0.682

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.538

GnomAD3 exomes

AF:

0.544

AC:

136602

AN:

251286

Hom.:

38692

AF XY:

0.549

AC XY:

74598

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.398

Gnomad AMR exome

AF:

0.413

Gnomad ASJ exome

AF:

0.585

Gnomad EAS exome

AF:

0.365

Gnomad SAS exome

AF:

0.485

Gnomad FIN exome

AF:

0.693

Gnomad NFE exome

AF:

0.617

Gnomad OTH exome

AF:

0.554

GnomAD4 exome

AF:

0.586

AC:

856788

AN:

1461716

Hom.:

255042

Cov.:

AF XY:

0.585

AC XY:

425316

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.393

Gnomad4 AMR exome

AF:

0.420

Gnomad4 ASJ exome

AF:

0.576

Gnomad4 EAS exome

AF:

0.357

Gnomad4 SAS exome

AF:

0.486

Gnomad4 FIN exome

AF:

0.692

Gnomad4 NFE exome

AF:

0.611

Gnomad4 OTH exome

AF:

0.564

GnomAD4 genome

AF:

0.530

AC:

80489

AN:

151868

Hom.:

22198

Cov.:

AF XY:

0.529

AC XY:

39307

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.398

Gnomad4 AMR

AF:

0.469

Gnomad4 ASJ

AF:

0.586

Gnomad4 EAS

AF:

0.373

Gnomad4 SAS

AF:

0.482

Gnomad4 FIN

AF:

0.682

Gnomad4 NFE

AF:

0.612

Gnomad4 OTH

AF:

0.537

Alfa

AF:

0.586

Hom.:

19838

Bravo

AF:

0.501

TwinsUK

AF:

0.604

AC:

2241

ALSPAC

AF:

0.611

AC:

2354

ESP6500AA

AF:

0.397

AC:

1750

ESP6500EA

AF:

0.601

AC:

5167

ExAC

AF:

0.548

AC:

66575

Asia WGS

AF:

0.439

AC:

1528

AN:

3478

EpiCase

AF:

0.595

EpiControl

AF:

0.591

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Benign:6

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25785002, 30071039, 27153395, 17028982, 19412175, 23222812, 23966609) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 04, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

1.4

DANN

Benign

0.90

DEOGEN2

Benign

0.061

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0000055

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.31

N;.

REVEL

Benign

0.11

Sift

Benign

0.17

T;.

Sift4G

Uncertain

0.059

T;T

Polyphen

0.031

B;.

Vest4

0.055

MutPred

0.13

Loss of MoRF binding (P = 0.0074);.;

MPC

0.11

ClinPred

0.0027

GERP RS

-1.0

Varity_R

0.087

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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