2-214752454-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000465.4(BARD1):c.1670G>C(p.Cys557Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,606,188 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 12 hom., cov: 32)

Exomes 𝑓: 0.021 ( 407 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 0.582

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=0.0048691034).

BP6

Variant 2-214752454-C-G is Benign according to our data. Variant chr2-214752454-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 8045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214752454-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2159/152264) while in subpopulation NFE AF= 0.0231 (1569/68026). AF 95% confidence interval is 0.0221. There are 12 homozygotes in gnomad4. There are 994 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2159 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.1670G>C	p.Cys557Ser	missense_variant	Exon 7 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.1670G>C	p.Cys557Ser	missense_variant	Exon 7 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2158

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00974

Gnomad FIN

AF:

0.00868

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0152

AC:

3811

AN:

251258

Hom.:

AF XY:

0.0158

AC XY:

2139

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00585

Gnomad ASJ exome

AF:

0.0237

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0132

Gnomad FIN exome

AF:

0.00963

Gnomad NFE exome

AF:

0.0231

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0213

AC:

30939

AN:

1453924

Hom.:

407

Cov.:

AF XY:

0.0212

AC XY:

15368

AN XY:

723714

show subpopulations

Gnomad4 AFR exome

AF:

0.00318

Gnomad4 AMR exome

AF:

0.00602

Gnomad4 ASJ exome

AF:

0.0230

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.0127

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.0245

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0142

AC:

2159

AN:

152264

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

994

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00364

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.0231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00975

Gnomad4 FIN

AF:

0.00868

Gnomad4 NFE

AF:

0.0231

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0200

Hom.:

Bravo

AF:

0.0136

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0238

AC:

205

ExAC

AF:

0.0156

AC:

1893

Asia WGS

AF:

0.00347

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Sep 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 12, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 24, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Jul 26, 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. 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]. -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

May 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Nov 18, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 07, 2019

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BARD1 p.Cys557Ser variant was identified in 466 of 24464 proband chromosomes (frequency: 0.019) from individuals or families with breast and ovarian (hereditary and sporadic) cancers, and was identified in 263 of 16634 chromosomes (frequency: 0.016) from healthy individuals (Ding 2011, Ghimenti 2002, Gonzalez_Hormazabal 2012). A meta-analysis done to assess if this variant was associated with increased risk of breast cancer found no evidence to support this association except in women with a strong family history where carriers were found to have a 3.4-fold increase of breast cancer risk (Gonzalez_Hormazabal 2012). In an Italian study looking at BRCA1 and BRCA2 negative HBOC families, the variant segregated with disease in 1 family, and through linkage anlaysis both BARD1 and BRCA2 were linked to disease in the family (Ghimenti 2002). Analysis of unselected breast and ovarian tumors identified the variant in an ovarian tumour in hemizyous state, with functional assays indicating it may contribute to cancer phenotype (Sauer 2005). The variant was also identified in dbSNP (ID: rs rs28997576) as â€šÃ„ÃºOtherâ€šÃ„Ã¹, ClinVar (classification benign by GeneDx, Ambry Genetics, Invitae, Color Genomics Inc., likely benign by Illumina, and as risk factor by OMIM), and Zhejiang Colon Cancer Database (9X) and not in Cosmic and MutDB databases. The variant was identified in control databases in 4197 of 277016 (55 homozygous) chromosomes at a frequency of 0.015 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), seen in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 238 of 10146 chromosomes (freq: 0.023), European (Non-Finnish) in 2914 of 126608 chromosomes (freq: 0.023), Other in 98 of 6456 chromosomes (freq: 0.015), and South Asian in 414 of 30782 chromosomes (freq: 0.013). The p.Cys557 residue is not conserved in mammals and four out of five 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

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

- -

Breast cancer, susceptibility to

Other:1

Aug 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

8.0

DANN

Benign

0.39

DEOGEN2

Benign

0.14

T;.;.;T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.81

T;T;T;T;.

MetaRNN

Benign

0.0049

T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

M;.;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.6

D;.;.;.;D

REVEL

Benign

0.14

Sift

Benign

0.30

T;.;.;.;T

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.040

B;.;.;.;.

Vest4

0.37

MutPred

0.13

Gain of phosphorylation at C557 (P = 0.0273);.;.;.;.;

MPC

0.093

ClinPred

0.011

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.067

gMVP

0.27

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

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