chr2-214728798-T-C

Position:

chr2-214728798-T-C

Variant summary

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

The NM_000465.4(BARD1):c.2212A>G(p.Ile738Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 1,614,204 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 91 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 2.38

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=0.0065450966).

BP6

Variant 2-214728798-T-C is Benign according to our data. Variant chr2-214728798-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214728798-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0075 (1143/152324) while in subpopulation AMR AF= 0.0131 (200/15290). AF 95% confidence interval is 0.0116. There are 9 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.2212A>G	p.Ile738Val	missense_variant	11/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.2212A>G	p.Ile738Val	missense_variant	11/11	1	NM_000465.4	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.00751

AC:

1143

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00577

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.00798

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.00774

AC:

1945

AN:

251344

Hom.:

AF XY:

0.00774

AC XY:

1051

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00317

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00839

Gnomad OTH exome

AF:

0.0187

GnomAD4 exome

AF:

0.00770

AC:

11262

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

5610

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00702

Gnomad4 AMR exome

AF:

0.0126

Gnomad4 ASJ exome

AF:

0.0279

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00318

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.00761

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.00750

AC:

1143

AN:

152324

Hom.:

Cov.:

AF XY:

0.00729

AC XY:

543

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00575

Gnomad4 AMR

AF:

0.0131

Gnomad4 ASJ

AF:

0.0233

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00798

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.00940

Hom.:

Bravo

AF:

0.00884

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.00732

AC:

889

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00971

EpiControl

AF:

0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

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	Nov 22, 2023	- -
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	- -
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]. -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2013	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. -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 18, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BARD1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

BARD1, EXON11, c.2212A>G, p.Ile738Val, Heterozygous, Benign The BARD1 p.Ile738Val variant was identified in 5 of 1030 proband chromosomes (frequency: 0.005) from Polish, Australian and Belgian individuals or families with high risk BRCA1/2 negative breast and/or ovarian cancer and was identified in 5 of 1096 control chromosomes (frequency:0.005) from healthy individuals (Ratajska 2012, Gorringe 2008, De Brakeleer 2010). The variant was identified in a breast tumour, and assessed to be a neutral variant based on a transient apoptosis assay that showed no loss of function (Sauer 2005). In addition, the variant is located with the BRCT functional domain(s) increasing the liklihood that it may have clinical significance; however, protein modelling showed no effect on protein structure or stability (De Brakeleer 2010). The variant was also identified in dbSBP (ID: rs61754118) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae, Vantari Genetics, Color Genomics, and Counsyl; and likely benign by Illumina), Clinivitae (4X) and the Zhejiang Colon Cancer Database (5x), but was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 2066 (21 homozygous) of 277076 chromosomes at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017); being identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 285 of 10150 chromosomes (freq: 0.028), Other in 119 of 6464 chromosomes (freq: 0.018), and Latino in 389 of 34408 chromosomes (freq: 0.011). The p.Ile738Val 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 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

0.12

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.10

T;.;.;.;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

T;T;T;T;T;.

MetaRNN

Benign

0.0065

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;.;.;.;.

MutationTaster

Benign

0.63

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.43

N;.;.;.;.;.

REVEL

Benign

0.011

Sift

Benign

0.40

T;.;.;.;.;.

Sift4G

Benign

0.53

T;T;T;T;T;T

Polyphen

0.027

B;.;.;.;.;.

Vest4

0.081

MVP

0.66

MPC

0.074

ClinPred

0.0056

GERP RS

4.5

Varity_R

0.036

gMVP

0.51

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