2-214728839-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000465.4(BARD1):c.2171C>T(p.Ala724Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,024 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A724E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 1 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: 9.56

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

breast cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
familial ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

BARD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.2171C>T	p.Ala724Val	missense_variant	Exon 11 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.2171C>T	p.Ala724Val	missense_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

251332

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112008

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Jun 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies are inconclusive: intermediate level of homology-directed repair activity compared to wild-type (PMID: 26350354); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31036035, 26350354, 33452952, 32881420, 36530327, 32658311, 32885271, 36243179, 17550235, 33606809) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BARD1 p.Ala724Val variant was not identified in the literature nor was it identified in the, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in dbSNP as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹. The variant was also identified in ClinVar and Clinvitae databases with uncertain significance by Ambry Genetics and Invitae; in the Cosmic database in a carcinoma of the large intestine. The variant was identified in control databases in 7 of 246096 chromosomes at a frequency of 0.00003 (Genome Aggregation Consortium Feb 27, 2017). The p.Ala724 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Val variant may impact the protein; however, this information is not predictive enough to assume 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. The variant is located with the BRCT functional domains, the clinical significance of which is unclear. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpretted as Uncertain significance and reported on 09-04-2019 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Mar 31, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:3

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 724 of the BARD1 protein (p.Ala724Val). This variant is present in population databases (rs587782662, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 31036035). ClinVar contains an entry for this variant (Variation ID: 142711). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BARD1 function (PMID: 26350354). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 19, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Nov 30, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A724V variant (also known as c.2171C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide position 2171. The alanine at codon 724 is replaced by valine, an amino acid with similar properties. This alteration has been reported in breast cancer patients (Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Sandoval RL et al. PLoS One, 2021 Mar;16:e0247363). This alteration was identified in a patient with high grade serous fallopian tube cancer who also carries the RAD51D c.82G>A alteration, classified as likely pathogenic by the authors, and the RAD51D c.629C>A alteration, classified as uncertain by the authors (Yang C et al. Breast Cancer Res Treat, 2021 Feb;185:869-877). In another study, this alteration was seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This alteration was also absent in 1229 Japanese patients with biliary tract cancer but present at a frequency of 0.001% in 37583 controls (Okawa Y et al. J Hepatol, 2023 Feb;78:333-342). Using a homology-directed repair (HDR) assay, this alteration demonstrated an intermediate reduction (59-66% of wildtype) in HDR activity (Lee C et al. Hum. Mutat. 2015 Dec;36(12):1205-14). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Feb 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with valine at codon 724 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that the variant protein causes a partial reduction in the homology-directed DNA repair activity (PMID: 26350354). An RNA splice study has reported that this variant does not impair RNA splicing (PMID: 33452952). This variant has been reported in individuals affected with breast cancer (PMID: 31036035, 32885271). This variant has been identified in 7/251332 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Sep 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BARD1 c.2171C>T (p.Ala724Val) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 1633792 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in BARD1 causing Breast Cancer (1.3e-05 vs 0.00025), allowing no conclusion about variant significance. c.2171C>T has been reported in the literature in individuals affected with Breast Cancer (example, Kwong_2020, Sandoval_2021, Weber-Lassalle_2019, Yang_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in a homology-directed repair assay in vitro (example, Lee_2015). The following publications have been ascertained in the context of this evaluation (PMID: 32068069, 26350354, 33606809, 31036035, 33452952). ClinVar contains an entry for this variant (Variation ID: 142711). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;.;.;.;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D;.

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.72

D;D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.

PhyloP100

9.6

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;.;.;.;.;.

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.66

MutPred

0.28

Gain of helix (P = 0.0325);.;.;.;.;.;

MVP

0.98

MPC

0.44

ClinPred

0.80

GERP RS

5.8

Varity_R

0.67

gMVP

0.60

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over