chr2-214781165-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting

The NM_000465.4(BARD1):c.709C>G(p.Gln237Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,579,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 1.94

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.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 41 uncertain in NM_000465.4

BP4

Computational evidence support a benign effect (MetaRNN=0.050822973).

BP6

Variant 2-214781165-G-C is Benign according to our data. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745. Variant chr2-214781165-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127745.

BS2

High AC in GnomAd4 at 7 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 rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.709C>G	p.Gln237Glu	missense_variant	Exon 4 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.709C>G	p.Gln237Glu	missense_variant	Exon 4 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000776

AC:

AN:

219116

AF XY:

0.000101

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:

0.000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

192

AN:

1427306

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

708182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31442

American (AMR)

AF:

0.00

AC:

AN:

36256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24004

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.00

AC:

AN:

78628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.000171

AC:

188

AN:

1100872

Other (OTH)

AF:

0.0000681

AC:

AN:

58740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000460

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.561

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.0000570

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Dec 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with ovarian cancer, a Lynch syndrome-related cancer and/or polyps, and breast cancer, as well as in unaffected controls (PMID: 33471991, 25980754, 34326862); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25186949, 29292755, 25980754, 33471991, 34326862) -

Jul 11, 2016

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: The BARD1 c.709C>G (p.Gln237Glu) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/114928 (1/10448), predominantly in the European (Non-Finnish) cohort, 11/64678 (1/5878), these frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188). The variant of interest was observed in an affected individual via a publication with limited information (ie, lack of cosegregation data) not allowing for an independent evaluation. Multiple clinical laboratories have cited the variant as "uncertain signficance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. -

Mar 14, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Jan 22, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Sep 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Familial cancer of breast

Uncertain:1Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 237 of the BARD1 protein (p.Gln237Glu). This variant is present in population databases (rs587780035, gnomAD 0.02%). This missense change has been observed in individual(s) with ovarian cancer and/or suspected Lynch syndrome (PMID: 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 127745). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Jul 22, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. 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]. -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BARD1-related cancer predisposition

Uncertain:1

Dec 15, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.5

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.044

T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.7

N;.

PhyloP100

1.9

PrimateAI

Benign

0.25

PROVEAN

Benign

0.68

N;.

REVEL

Benign

0.17

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.053

MutPred

0.18

Loss of loop (P = 0.0804);.;

MVP

0.81

MPC

0.081

ClinPred

0.022

GERP RS

4.9

Varity_R

0.052

gMVP

0.090

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over