2-214745773-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_000465.4(BARD1):c.1759G>A(p.Glu587Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E587D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.24

Publications

3 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-214745773-C-T is Benign according to our data. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782. Variant chr2-214745773-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406782.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.1759G>A	p.Glu587Lys	missense_variant	Exon 8 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.1759G>A	p.Glu587Lys	missense_variant	Exon 8 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251328

AF XY:

0.00000736

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111960

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:1

Jul 28, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glutamic acid with lysine at codon 587 of the BARD1 protein (p.Glu587Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs780820468, ExAC 0.006%) but has not been reported in the literature in individuals with a BARD1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 05, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E587K variant (also known as c.1759G>A), located in coding exon 8 of the BARD1 gene, results from a G to A substitution at nucleotide position 1759. The glutamic acid at codon 587 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.060

T;.;.;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.82

T;T;T;T;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.093

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.040

N;.;.;.;.

PhyloP100

1.2

PrimateAI

Benign

0.39

PROVEAN

Benign

0.99

N;.;.;.;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;.;.;.;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0040

B;.;.;.;.

Vest4

0.19

MutPred

0.56

Gain of MoRF binding (P = 0.0079);.;.;.;.;

MVP

0.76

MPC

0.085

ClinPred

0.028

GERP RS

3.3

Varity_R

0.082

gMVP

0.57

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.38

Position offset: 3

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over