2-214752539-G-A

Position:

chr2-214752539-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_000465.4(BARD1):c.1585C>T(p.Arg529Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.53

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

BS2

High AC in GnomAd4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.1585C>T	p.Arg529Trp	missense_variant	7/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.1585C>T	p.Arg529Trp	missense_variant	7/11	1	NM_000465.4	ENSP00000260947	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251232

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460900

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2022	This missense variant replaces arginine with tryptophan at codon 529 of the BARD1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 13/282628 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2023	The p.R529W variant (also known as c.1585C>T), located in coding exon 7 of the BARD1 gene, results from a C to T substitution at nucleotide position 1585. The arginine at codon 529 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 08, 2022	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27960086, 31036035) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 11, 2018	- -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 529 of the BARD1 protein (p.Arg529Trp). This variant is present in population databases (rs375515606, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185032). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 03, 2023

Variant summary: BARD1 c.1585C>T (p.Arg529Trp) results in a non-conservative amino acid change in 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 4e-05 in 251232 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BARD1 causing Breast Cancer (4e-05 vs 0.00025), allowing no conclusion about variant significance. c.1585C>T has been reported in the literature in individuals affected with BARD1-associated cancers (e.g, Akcay_2021, Bono_2021), however without strong evidence for causality (e.g., lack of co-occurrence and co-segregation data). Additionally the variant has been reported in the literature in several unaffected controls (e.g., Weber-Lasalle_2019, Bucalo_2023). These reports therefore do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 34371384, 37262986, 31036035). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

BARD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 29, 2024

The BARD1 c.1585C>T variant is predicted to result in the amino acid substitution p.Arg529Trp. This variant has been reported as a variant of uncertain significance in the germline of two individuals with breast cancer (Table S1, Bono et al. 2021. PubMed ID: 34371384; Table S6, Akcay et al. 2020. PubMed ID: 32658311). It has also been reported in controls in two studies, one of which investigated the risk of breast cancer in an Italian cohort and the other assessing BARD1 loss of function variant association with early-onset breast cancer (Table S5, Bucalo et al. 2023. PubMed ID: 37262986; Table S4, Weber-Lassalle et al. 2019. PubMed ID: 31036035). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and is listed in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/185032/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.;T;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.97

D;D;D;D;.

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.5

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.0

D;.;.;.;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;.;.;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.84

MVP

0.98

MPC

0.44

ClinPred

0.87

GERP RS

3.8

Varity_R

0.70

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: 16

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