2-214792327-G-A

Position:

chr2-214792327-G-A

Variant summary

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

The NM_000465.4(BARD1):c.334C>T(p.Arg112*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,920 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

BARD1
NM_000465.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.80

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:

BARD1 (HGNC:):

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 2-214792327-G-A is Pathogenic according to our data. Variant chr2-214792327-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 185139.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.334C>T	p.Arg112*	stop_gained	3/11	ENST00000260947.9	NP_000456.2	Q99728-1A0AVN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.334C>T	p.Arg112*	stop_gained	3/11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151596

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251010

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461324

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726952

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:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151596

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74006

show subpopulations

Gnomad4 AFR

AF:

0.0000485

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000802

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change creates a premature translational stop signal (p.Arg112*) 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 (rs758972589, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with neuroblastoma (PMID: 23334666, 27083178). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 185139). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 18, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 26, 2021	This nonsense variant causes the premature termination of BARD1 protein synthesis. It has been described in individuals with breast cancer and neuroblastoma in the published literature (PMIDs: 31036035 (2019), 30781715 (2019), 28724667 (2017), 27083178 (2016), and 23334666 (2013)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 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 breast and/or ovarian cancer (PMID: 27083178, 28724667, 31036035, 32679805, 28888541); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23334666, 28985766, 27083178, 28055978, 28152038, 28724667, 29292755, 31036035, 32679805, 28888541, 29922827, 32427313) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 3 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 identified in 2/251010 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	clinical testing	Ambry Genetics	Aug 03, 2022	The p.R112* pathogenic mutation (also known as c.334C>T), located in coding exon 3 of the BARD1 gene, results from a C to T substitution at nucleotide position 334. This changes the amino acid from an arginine to a stop codon within coding exon 3. This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun L et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119), and has been reported in 1 of 124 patients with stage II-III triple negative breast cancer (González-Rivera M et al. Breast Cancer Res. Treat. 2016 Apr;156:507-515). This alteration has also been reported as a germline mutation in a cohort of patients with neuroblastoma tumors (Pugh TJ et al. Nat. Genet. 2013 Mar; 45(3):279-84. 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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Malignant tumor of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 15, 2022

Variant summary: BARD1 c.334C>T (p.Arg112X) 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 1.5e-05 in 259978 control chromosomes (gnomAD and Palmer_2020). c.334C>T has been reported in the literature in multiple individuals affected with breast cancer (e.g. Gonzalez-Rivera_ 2016, Tavera-Tapia_2017, Sun_2017, Weber-Lassalle_2019) and in individuals with neuroblastoma and ovarian cancer (e.g.Pugh_2013, Lilyquist_2017). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories and a professional group (CZECANCA consortium) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified 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

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.86

Vest4

0.89

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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