rs28997575

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_000465.4(BARD1):c.1075_1095delTTGCCTGAATGTTCTTCACCA(p.Leu359_Pro365del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,614,032 control chromosomes in the GnomAD database, including 759 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L359L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.028 ( 85 hom., cov: 32)

Exomes 𝑓: 0.022 ( 674 hom. )

Consequence

BARD1
NM_000465.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.10

Publications

19 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 -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000465.4.

BP6

Variant 2-214780778-GTGGTGAAGAACATTCAGGCAA-G is Benign according to our data. Variant chr2-214780778-GTGGTGAAGAACATTCAGGCAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 140795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.1075_1095delTTGCCTGAATGTTCTTCACCA	p.Leu359_Pro365del	conservative_inframe_deletion	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.1075_1095delTTGCCTGAATGTTCTTCACCA	p.Leu359_Pro365del	conservative_inframe_deletion	Exon 4 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4294

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0404

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0379

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.0478

Gnomad SAS

AF:

0.0774

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0289

AC:

7261

AN:

251308

AF XY:

0.0304

show subpopulations

Gnomad AFR exome

AF:

0.0432

Gnomad AMR exome

AF:

0.0337

Gnomad ASJ exome

AF:

0.0120

Gnomad EAS exome

AF:

0.0439

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0324

GnomAD4 exome

AF:

0.0224

AC:

32769

AN:

1461824

Hom.:

674

AF XY:

0.0238

AC XY:

17297

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0432

AC:

1447

AN:

33480

American (AMR)

AF:

0.0340

AC:

1521

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

313

AN:

26134

East Asian (EAS)

AF:

0.0583

AC:

2312

AN:

39690

South Asian (SAS)

AF:

0.0714

AC:

6162

AN:

86258

European-Finnish (FIN)

AF:

0.00311

AC:

166

AN:

53412

Middle Eastern (MID)

AF:

0.0349

AC:

201

AN:

5766

European-Non Finnish (NFE)

AF:

0.0171

AC:

19005

AN:

1111980

Other (OTH)

AF:

0.0272

AC:

1642

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

2178

4356

6533

8711

10889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

802

1604

2406

3208

4010

<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:

0.0282

AC:

4294

AN:

152208

Hom.:

Cov.:

AF XY:

0.0284

AC XY:

2112

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0405

AC:

1681

AN:

41522

American (AMR)

AF:

0.0379

AC:

579

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.0477

AC:

247

AN:

5174

South Asian (SAS)

AF:

0.0776

AC:

374

AN:

4818

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0183

AC:

1246

AN:

68004

Other (OTH)

AF:

0.0308

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

199

399

598

798

997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.00648

Hom.:

Bravo

AF:

0.0308

Asia WGS

AF:

0.0570

AC:

196

AN:

3478

EpiCase

AF:

0.0230

EpiControl

AF:

0.0226

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Benign:7

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2016

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 04, 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

- -

Feb 24, 2023

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]. -

not specified

Benign:4

Jul 08, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 19, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BARD1 p.Leu359_Pro365del variant was identified in 19 of 926 proband chromosomes (frequency: 0.0205) from individuals or families with hereditary breast and ovarian cancer and was present in 4 of 140 control chromosomes (frequency: 0.03) from healthy individuals, and is reported in the literature as a polymorphism (De Brakeleer 2010, De Brakeleer 2015, Ishitobi 2003, Liu 2017, Irminger-Finger 2015). The variant was also identified in ClinVar as benign (by Ambry Genetics, GeneDx, Invitae, and Counsyl), and the Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 7807 of 277012 chromosomes at a frequency of 0.03 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: South Asian (52 homozygous) in 2152 of 30774 chromosomes (freq: 0.07), East Asian (8 homozygous) in 834 of 18854 chromosomes (freq: 0.044), African (9 homozygous) in 986 of 24026 chromosomes (freq: 0.041), Latino (2 homozygous) in 1167 of 34380 chromosomes (freq: 0.034), Other in 209 of 6462 chromosomes (freq: 0.032), European (Non-Finnish) in 2254 of 126574 chromosomes (freq: 0.018), Ashkenazi Jewish in 118 of 10152 chromosomes (freq: 0.012). This variant is an in-frame deletion resulting in the removal of a 7 amino acid residues from codon 359 to 365; the impact of this alteration on BARD1 protein function is not known. 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 cancer-predisposing syndrome

Benign:4

Sep 17, 2012

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Nov 14, 2014

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=172/28

polymorphism (auto)

(source)

Splicing

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