2-214730457-T-TCATACTTTTCTTCCTGTTCA

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000465.4(BARD1):c.1935_1954dupTGAACAGGAAGAAAAGTATG(p.Glu652ValfsTer69) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000905 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

BARD1
NM_000465.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 6.51

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.163 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 2-214730457-T-TCATACTTTTCTTCCTGTTCA is Pathogenic according to our data. Variant chr2-214730457-T-TCATACTTTTCTTCCTGTTCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.1935_1954dupTGAACAGGAAGAAAAGTATG	p.Glu652ValfsTer69	frameshift_variant	Exon 10 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.1935_1954dupTGAACAGGAAGAAAAGTATG	p.Glu652ValfsTer69	frameshift_variant	Exon 10 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251374

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135858

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000937

AC:

137

AN:

1461736

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:8

Apr 13, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 07, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2018

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu652Valfs*69) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the BARD1 protein. This variant is present in population databases (rs587780024, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 20077502, 25452441, 26681312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127725). RT-PCR analysis has shown that this variant did not activate nonsense mediated decay, as equal amounts of the mutant and wild-type alleles were expressed in the leukocytes of affected individuals (PMID: 20077502). This truncating variant does lead to the loss of the last 126 amino acids of the BARD1 protein (Glu652-Ser777), removing completely the most C-terminal of the two BRCT repeats (residues 669-777) (PMID: 26315354, 17550235). While the functional significance of deleting the second BRCT domain has not been addressed experimentally, studies suggest that both BRCT repeats in BARD1 are necessary for its normal functioning (PMID: 17550235, 26738429, 17848578). For these reasons, this variant has been classified as Pathogenic. -

Feb 24, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Feb 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Dec 02, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 126 amino acids are replaced with 68 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with personal or family history of breast and/or ovarian cancer (PMID: 20077502, 25452441, 28888541, 29790872, 31173646, 31036035, 35626031); This variant is associated with the following publications: (PMID: 31341520, 26681312, 28008555, 26738429, 28152038, 20077502, 25452441, 26556299, 26315354, 17848578, 26546047, 29922827, 29790872, 31036035, 31173646, 33099839, 32679805, 33598691, 35626031, 32923906, 36187937, 28888541, 34326862, 35969835, 17550235, 37688579) -

Dec 20, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant alters the translational reading frame of the BARD1 mRNA and causes the premature termination of BARD1 protein synthesis. The frequency of this variant in the general population, 0.00012 (15/129114 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with breast cancer (PMIDs: 31036035 (2019), 26681312 (2015), 25452441 (2015), 20077502 (2010)). Based on the available information, this variant is classified as pathogenic. -

Nov 03, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong; PP1; PS4_SUP -

Dec 15, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1935_1954dup20 pathogenic mutation, located in coding exon 10 of the BARD1 gene, results from a duplication of 20 nucleotides from positions 1935 to 1954, causing a translational frameshift with a predicted alternate stop codon. This mutation has previously been reported in a high risk breast/ovarian cancer family from Belgium (De Brakeleer S et al. Hum. Mutat. 2010 Mar;31(3):E1175-85) and in 3 of 1824 triple negative breast cancer patients unselected for family history (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11, Supplementary Data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Feb 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 20 nucleotides in exon 10 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to disrupt the last 126 amino acids of the BARD1 protein, including the functionally important BRCT2 domain (a.a. 667-777) (PMID: 17848578) and is likely to result in a non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 20077502, 25452441, 26681312, 31036035). This variant has also been reported in at least one individual with neuroblastoma (PMID: 33598691). This variant has been identified in 17/282768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Nov 10, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BARD1 c.1935_1954dup20 (p.Glu652ValfsX69) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One report in the literature indicates that the variant does not activate nonsense mediated decay, as RT-PCR analysis showed equal amounts of the mutant and wild-type alleles expressed in leukocytes from individuals with the variant (DeBrakeleer_2010). The variant allele was found at a frequency of 6.4e-05 in 251374 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer (6.4e-05 vs 0.00025), allowing no conclusion about variant significance. c.1935_1954dup20 has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. DeBrakeleer_2010, Couch_2015, Weber-Lassalle_2019). These data indicate that the variant is very likely to be associated with disease. The variant has also been found in at least one patient with pancreatic cancer (Smith_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 12, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (strong pathogenic): As per PVS1 decision tree von Tayoun (2018): Nonsense or Frameshift --> Not predicted to undergo NMD Truncated/altered region is critical to protein function PVS1_Strong, PS3 (medium pathogenic): ClinVar Invitae/LapCorp 2024: While the functional significance of deleting the second BRCT domain has not been addressed experimentally, studies suggest that both BRCT repeats in BARD1 are necessary for its normal functioning (PMID: 17550235, 26738429, 17848578) --> PS3 ?? Adamovich et al. PMID: 30925164 V767fs LOF in HDR-, Cisplatin- and IR-Assay Toh et al. PMID: 31371347 FS AA 612 impaired Protein function, PM1 (medium pathogenic): PTC, in mutational hotspot -

Malignant tumor of breast

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 09-21-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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