2-214752472-G-C

Position:

chr2-214752472-G-C

Variant summary

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

The NM_000465.4(BARD1):c.1652C>G(p.Ser551Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,030 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

BARD1
NM_000465.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.02

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 2-214752472-G-C is Pathogenic according to our data. Variant chr2-214752472-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.1652C>G	p.Ser551Ter	stop_gained	7/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.1652C>G	p.Ser551Ter	stop_gained	7/11	1	NM_000465.4	ENSP00000260947	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251344

Hom.:

AF XY:

0.00000736

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:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1460880

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726780

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:

0.0000621

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 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	Counsyl	Dec 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change creates a premature translational stop signal (p.Ser551*) 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 (rs587781707, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25428789, 26786923). ClinVar contains an entry for this variant (Variation ID: 141384). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2020	Variant summary: BARD1 c.1652C>G (p.Ser551X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251344 control chromosomes (gnomAD). c.1652C>G has been reported in the literature in multiple individuals affected with Breast Cancer (e.g. Churpek_2015, Li_2016, Maxwell_2015, Thompson_2016, Weber-Lassalle_2019, Tung_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to be deficient/non-functional in a homology-directed repair assay (Adamovich_2019). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2022	The p.S551* pathogenic mutation (also known as c.1652C>G), located in coding exon 7 of the BARD1 gene, results from a C to G substitution at nucleotide position 1652. This changes the amino acid from a serine to a stop codon within coding exon 7. This alteration has been previously identified in various high risk breast-ovarian, triple negative breast, and pancreatic cancer cohorts (Churpek JE et al. Breast Cancer Res. Treat., 2015 Jan;149:31-9; Maxwell KN et al. Genet. Med., 2015 Aug;17:630-8; Thompson ER et al. J. Clin. Oncol., 2016 May;34:1455-9; Li J et al. J. Med. Genet., 2016 Jan;53:34-42; Brand R et al. Cancer. 2018 Sep;124(17):3520-3527). 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	This variant changes 1 nucleotide in exon 7 of the BARD1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant results in the loss of homology-directed DNA repair activity of the BARD1 protein (PMID: 30925164 ). This variant has been reported in individuals affected with familial breast cancer (PMID 25428789, 25503501, 26534844, 26786923, 31036035). This variant has been identified in 3/251344 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 08, 2021	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2024	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; Observed in individuals with a personal or family history including breast, ovarian, and other cancers (PMID: 25428789, 25503501, 26534844, 26786923, 31036035, 33498765); Published functional studies demonstrate reduced homology-directed repair (PMID: 30925164); A case control meta-analysis suggests this variant is associated with breast cancer (PMID: 32679805); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28152038, 26534844, 36315097, 35833951, 34887416, 36451132, 25428789, 26681312, 26786923, 25503501, 28873162, 29625052, 32561076, 30067863, 32338768, 31036035, 33498765, 29922827, 30925164, 33804961, 31794323, 32679805, 25186627) -

Breast cancer, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 19, 2016

- -

BARD1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The BARD1 c.1652C>G variant is predicted to result in premature protein termination (p.Ser551*). This variant has been reported in multiple individuals with breast cancer (Churpek et al. 2015. PubMed ID: 25428789; Weber-Lassalle N et al. 2019. PubMed ID: 31036035; Tung N et al. 2014. PubMed ID: 25186627; Maxwell KN et al. 2014. PubMed ID: 25503501; Thompson ER et al. 2016. PubMed ID: 26786923). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141384/). Nonsense variants in BARD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A

Vest4

0.97

GERP RS

3.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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