Genetic Variant NM_000465.4:c.1518T>C (chr2-214767532-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000465.4(BARD1):c.1518T>C(p.His506His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,612,710 control chromosomes in the GnomAD database, including 522,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 44244 hom., cov: 32)

Exomes 𝑓: 0.81 ( 478353 hom. )

Consequence

BARD1
NM_000465.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -0.241

Publications

42 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-214767532-A-G is Benign according to our data. Variant chr2-214767532-A-G is described in ClinVar as Benign. ClinVar VariationId is 183704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.241 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

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.1518T>C	p.His506His	synonymous	Exon 6 of 11	NP_000456.2
BARD1	NM_001282543.2		c.1461T>C	p.His487His	synonymous	Exon 5 of 10	NP_001269472.1
BARD1	NM_001282545.2		c.216-14977T>C		intron	N/A	NP_001269474.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BARD1	ENST00000260947.9	TSL:1 MANE Select	c.1518T>C	p.His506His	synonymous	Exon 6 of 11	ENSP00000260947.4
BARD1	ENST00000617164.5	TSL:1	c.1461T>C	p.His487His	synonymous	Exon 5 of 10	ENSP00000480470.1
BARD1	ENST00000613706.5	TSL:1	c.1110T>C	p.His370His	synonymous	Exon 6 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes

AF:

0.756

AC:

114859

AN:

151980

Hom.:

44222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.599

Gnomad AMI

AF:

0.757

Gnomad AMR

AF:

0.754

Gnomad ASJ

AF:

0.829

Gnomad EAS

AF:

0.949

Gnomad SAS

AF:

0.840

Gnomad FIN

AF:

0.899

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.805

Gnomad OTH

AF:

0.737

GnomAD2 exomes

AF:

0.817

AC:

205304

AN:

251312

AF XY:

0.819

show subpopulations

Gnomad AFR exome

AF:

0.597

Gnomad AMR exome

AF:

0.816

Gnomad ASJ exome

AF:

0.827

Gnomad EAS exome

AF:

0.954

Gnomad FIN exome

AF:

0.893

Gnomad NFE exome

AF:

0.806

Gnomad OTH exome

AF:

0.793

GnomAD4 exome

AF:

0.808

AC:

1179667

AN:

1460612

Hom.:

478353

Cov.:

AF XY:

0.810

AC XY:

588295

AN XY:

726672

show subpopulations

African (AFR)

AF:

0.584

AC:

19504

AN:

33410

American (AMR)

AF:

0.808

AC:

36112

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.824

AC:

21520

AN:

26124

East Asian (EAS)

AF:

0.940

AC:

37320

AN:

39692

South Asian (SAS)

AF:

0.841

AC:

72547

AN:

86228

European-Finnish (FIN)

AF:

0.891

AC:

47598

AN:

53406

Middle Eastern (MID)

AF:

0.756

AC:

4358

AN:

5766

European-Non Finnish (NFE)

AF:

0.804

AC:

892986

AN:

1110916

Other (OTH)

AF:

0.791

AC:

47722

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

11772

23544

35315

47087

58859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20778

41556

62334

83112

103890

<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:

0.756

AC:

114924

AN:

152098

Hom.:

44244

Cov.:

AF XY:

0.761

AC XY:

56575

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.599

AC:

24846

AN:

41452

American (AMR)

AF:

0.754

AC:

11520

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.829

AC:

2876

AN:

3470

East Asian (EAS)

AF:

0.949

AC:

4907

AN:

5172

South Asian (SAS)

AF:

0.839

AC:

4050

AN:

4826

European-Finnish (FIN)

AF:

0.899

AC:

9525

AN:

10590

Middle Eastern (MID)

AF:

0.765

AC:

225

AN:

294

European-Non Finnish (NFE)

AF:

0.805

AC:

54726

AN:

67990

Other (OTH)

AF:

0.740

AC:

1562

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1383

2766

4150

5533

6916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.762

Hom.:

33481

Bravo

AF:

0.738

Asia WGS

AF:

0.861

AC:

2994

AN:

3478

EpiCase

AF:

0.793

EpiControl

AF:

0.795

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cancer of breast (6)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

not specified (2)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.0

(source)

DANN

Benign

0.41

PhyloP100

-0.24

Mutation Taster

=98/2

polymorphism (auto)

(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

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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

Computational scores

Splicing

Publications

Other links and lift over