Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I738T) has been classified as Uncertain significance.

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:21

Conservation

PhyloP100: 2.38

Publications

31 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 136501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1143 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BARD1	NM_000465.4	MANE Select	c.2212A>G	p.Ile738Val	missense	Exon 11 of 11	NP_000456.2
BARD1	NM_001282543.2		c.2155A>G	p.Ile719Val	missense	Exon 10 of 10	NP_001269472.1
BARD1	NM_001282545.2		c.859A>G	p.Ile287Val	missense	Exon 7 of 7	NP_001269474.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BARD1	ENST00000260947.9	TSL:1 MANE Select	c.2212A>G	p.Ile738Val	missense	Exon 11 of 11	ENSP00000260947.4
BARD1	ENST00000617164.5	TSL:1	c.2155A>G	p.Ile719Val	missense	Exon 10 of 10	ENSP00000480470.1
BARD1	ENST00000613706.5	TSL:1	c.1804A>G	p.Ile602Val	missense	Exon 11 of 11	ENSP00000484976.2

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

GnomAD2 exomes

AF:

0.00774

AC:

1945

AN:

251344

AF XY:

0.00774

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 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

African (AFR)

AF:

0.00702

AC:

235

AN:

33478

American (AMR)

AF:

0.0126

AC:

562

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0279

AC:

728

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00318

AC:

274

AN:

86258

European-Finnish (FIN)

AF:

0.000899

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0482

AC:

278

AN:

5768

European-Non Finnish (NFE)

AF:

0.00761

AC:

8461

AN:

1112002

Other (OTH)

AF:

0.0112

AC:

676

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

707

1414

2120

2827

3534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.00750

AC:

1143

AN:

152324

Hom.:

Cov.:

AF XY:

0.00729

AC XY:

543

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00575

AC:

239

AN:

41574

American (AMR)

AF:

0.0131

AC:

200

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00310

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00798

AC:

543

AN:

68028

Other (OTH)

AF:

0.0189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00903

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cancer of breast (7)

Hereditary cancer-predisposing syndrome (5)

not specified (5)

not provided (2)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

2.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.43

REVEL

Benign

0.011

Sift

Benign

0.40

Sift4G

Benign

0.53

Polyphen

0.027

Vest4

0.081

MVP

0.66

MPC

0.074

ClinPred

0.0056

GERP RS

4.5

Varity_R

0.036

gMVP

0.51

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs61754118

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over