rs2228456

Positions:

chr2-214730479-A-G

Variant summary

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

The NM_000465.4(BARD1):c.1933T>C(p.Cys645Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,613,948 control chromosomes in the GnomAD database, including 198 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 0.020 ( 104 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 94 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 1.56

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=0.00192523).

BP6

Variant 2-214730479-A-G is Benign according to our data. Variant chr2-214730479-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 142135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0652 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.1933T>C	p.Cys645Arg	missense_variant	10/11	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.1933T>C	p.Cys645Arg	missense_variant	10/11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2994

AN:

152116

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0673

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00929

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.00523

AC:

1314

AN:

251364

Hom.:

AF XY:

0.00372

AC XY:

506

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0702

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00210

AC:

3063

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1313

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.0683

Gnomad4 AMR exome

AF:

0.00313

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000543

Gnomad4 NFE exome

AF:

0.000164

Gnomad4 OTH exome

AF:

0.00525

GnomAD4 genome

AF:

0.0197

AC:

2999

AN:

152234

Hom.:

104

Cov.:

AF XY:

0.0190

AC XY:

1416

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0673

Gnomad4 AMR

AF:

0.00928

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.00389

Hom.:

Bravo

AF:

0.0217

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0670

AC:

295

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00639

AC:

776

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Benign:7

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 2023	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. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
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	Fulgent Genetics, Fulgent Genetics	May 24, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2016	Variant summary:The c.1933T>C variant involves the alteration of a non-conserved nucleotide and causes change from medium size and polar (C) residue to large size and basic. 4/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 1% (779/121331 chromosomes), predominantly observed in the African subpopulation at a frequency of 6.9% (720/10388 chromosomes) including 31 African homozygous occurrences. These frequencies exceed the maximal expected allele frequency for a pathogenic BARD1 variant of 0.0218%, suggesting this is a benign polymorphism found primarily in populations of African origin. One reputable clinical lab has classified this variant as benign (Ambry Genetics). It has previously been reported in patients with breast and ovarian cancer (Sauer 2005) without strong evidence for causality. Functional analyses showed this variant decreased the tumor suppression activity and apoptosis (Sauer 2005) and decreased the binding activity with poly(ADP-ribose) and BRCA1 (Li 2013). However, the in vivo implications of these functional findings have not been confirmed yet. Considering all, especially based on the high allele frequency in population cohorts, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 25, 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 18, 2014	- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BARD1 p.Cys645Arg variant was identified in 1 of 504 proband chromosomes (frequency: 0.00198) from individuals or families with hereditary breast and ovarian cancer, and was also identified in 3 of 472 control chromosomes (frequency: 0.006) (De Brakeleer_2010_20077502, Sauer_2005_16061562). The variant was also identified in the following databases: dbSNP (ID: rs2228456) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (as likely benign by Illumina and benign by Ambry Genetics, Color Genomics, Counsyl, Invitae, and Quest Diagnostics), Clinvitae (3x), and Zhejiang Colon Cancer Database (3x). The variant was not identified in Cosmic, or MutDB databases. The variant was identified in control databases in 1841 of 277108 chromosomes (56 homozygous) at a frequency of 0.006644 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1657 (55 homozygous) of 24032 chromosomes (freq: 0.06895), â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 23 (1 homozygous) of 6464 chromosomes (freq: 0.003558), Latino in 99 of 34416 chromosomes (freq: 0.002877), European (Non-Finnish) in 29 of 126612 chromosomes (freq: 0.000229), Ashkenazi Jewish in 14 of 10148 chromosomes (freq: 0.00138), European (Finnish) in 17 of 25784 chromosomes (freq: 0.000659), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), while the variant was not observed in the East Asian populations. Several functional studies identified the variant to be associated with breast and ovarian cancer, and may adversely affect the structure and function of the BRCT1 domain (Alshatwi_2012_23056176, Birrane_2007_17550235, Li_2013_23680151, Sauer_2005_16061562). The p.Cys645Arg residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

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

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.077

T;.;.;.;T;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.73

T;T;T;T;T;.;.

MetaRNN

Benign

0.0019

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.35

N;.;.;.;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

N;.;.;.;.;.;N

REVEL

Benign

0.048

Sift

Benign

0.87

T;.;.;.;.;.;T

Sift4G

Benign

0.90

T;T;T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.;.;.

Vest4

0.14

MVP

0.36

MPC

0.13

ClinPred

0.0027

GERP RS

4.6

Varity_R

0.25

gMVP

0.69

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