rs587780021

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000465.4(BARD1):c.1690C>T(p.Gln564Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000248 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q564Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

BARD1
NM_000465.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24U:1

Conservation

PhyloP100: 4.84

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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-214745842-G-A is Pathogenic according to our data. Variant chr2-214745842-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.1690C>T	p.Gln564Ter	stop_gained	8/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.1690C>T	p.Gln564Ter	stop_gained	8/11	1	NM_000465.4	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152092

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251300

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135824

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:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:8Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Gln564*) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). This variant is present in population databases (rs587780021, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 21344236, 25994375, 26010302, 26315354, 26329992, 26681312, 27443514). ClinVar contains an entry for this variant (Variation ID: 127720). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS3, PS4_STR -
Uncertain significance, flagged submission	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 23, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2023	- -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: significantly reduced homology-directed repair and may result in abnormal splicing (Ratajska 2015, Adamovich 2019); Case control studies suggest this variant is associated with breast cancer (Suszynska 2019); Observed in multiple individuals with personal and/or family history of breast, ovarian, colorectal, or endometrial cancer (Ratajska 2012, Blazer 2015, De Brakeleer 2015, Klonowska 2015, Ramus 2015, Maxwell 2016, Ring 2016, Weber-Lassalle 2019); This variant is associated with the following publications: (PMID: 25330149, 26075229, 26083025, 27443514, 31371347, 26681312, 31589614, 29922827, 28888541, 32726901, 21344236, 26010302, 25994375, 25980754, 26539620, 26738429, 26315354, 28030839, 27153395, 26329992, 30925164, 31036035, 28008555, 30675285, 31173646, 31142030, 29506128, 30947698, 31159747, 29625052, 26689913) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant results in the creation of a premature translational stop signal at codon 564 of the BARD1 protein (p.Gln564*). It is expected to result in absent or disrupted protein product. This variant has been described in the literature in patients with a strong family or personal history of breast and/or ovarian cancer (PMID: 21344236, PMID: 25994375, PMID: 26010302).The mutation database ClinVar contains an entry for this variant (Variation ID: 127720). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BARD1: PVS1, PS4 -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2021	The p.Q564* pathogenic mutation (also known as c.1690C>T), located in coding exon 8 of the BARD1 gene, results from a C to T substitution at nucleotide position 1690. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration has been reported in numerous patients diagnosed with breast and/or ovarian cancer (Ratajska M et al. Breast Cancer Res. Treat. 2012 Jan;131:89-97; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Klonowska K et al. Sci. Rep. 2015 May;5:10424; Ramus SJ et al. J Natl Cancer Inst. 2015 Nov;107:; Weber-Lassalle N et al. Breast Cancer Res. 2019 04;21:55; Shahi RB et al. BMC Cancer. 2019 Apr;19:313). Additionally, this alteration has been identified in a patient with triple-negative breast cancer (De Brakeleer S et al. Clin. Genet. 2016 Mar;89(3):336-40) and a male breast cancer patient (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 06, 2023	This variant changes 1 nucleotide in exon 8 of the BARD1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 15 individuals affected with breast or ovarian cancer (PMID: 25994375, 26010302, 26315354, 26329992, 26681312, 28008555, 29625052, 30947698, 31036035, 32679805, 37239058, 37563628) and one individual affected with endometrial cancer (PMID: 27443514). In a large breast cancer case-control meta analysis, this variant has been observed in 17/60449 cases and 6/53455 controls (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000187). This variant has been identified in 7/282686 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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

BARD1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2023

The BARD1 c.1690C>T variant is predicted to result in premature protein termination (p.Gln564*). This variant has been reported in many individuals with breast and/or ovarian cancer (Ratajska et al 2012. PubMed ID: 21344236; Yurgelun MB et al 2015. PubMed ID: 25980754; Klonowska K et al 2015. PubMed ID: 25994375; Ratajska M et al 2015. PubMed ID: 26329992; Lu C et al 2015. PubMed ID: 26689913; Maxwell KN et al 2016. PubMed ID: 27153395; Lilyquist J et al 2017. PubMed ID: 28888541; Lowery MA et al 2018. PubMed ID: 29506128; Huang KL et al 2018. PubMed ID: 29625052; Shahi RB et al 2019. PubMed ID: 30947698; Weber-Lassalle N et al 2019. PubMed ID: 31036035; Tsaousis GN et al 2019. PubMed ID: 31159747). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-215610566-G-A) and is interpreted as pathogenic (15) and uncertain significance (1) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127720/). Nonsense variants in BARD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Triple-Negative Breast Cancer Finding

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Lab. Molecular Oncology, VUB, Free University of Brussels

Feb 01, 2015

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 10, 2019

Variant summary: BARD1 c.1690C>T (p.Gln564X) 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. 5/5 computational tools predict no significant impact on normal splicing. However, Ratajska_2015 report that this variant may have an impact on splicing alteration. The variant allele was found at a frequency of 2.4e-05 in 252390 control chromosomes (gnomAD). c.1690C>T has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer patients (e.g. Cybulski_2014, Weber-Lassalle_2019). These data indicate that the variant is very likely to be associated with disease. Nine other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Endometrial carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Feb 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

A;A

Vest4

0.89

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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