rs752514155

Variant names:

• chr2-214809515-C-A
• rs752514155
• NM_000465.4:c.55G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-214809515-C-A
• chr2-214809515-C-G
• chr2-214809515-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_000465.4(BARD1):​c.55G>T​(p.Glu19*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 1,597,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E19E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: BARD1 NM_000465.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: -0.647
• Publications: 3 publications found

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]

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 517 pathogenic variants in the truncated region.
• PP5: Variant 2-214809515-C-A is Pathogenic according to our data. Variant chr2-214809515-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 233594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.55G>T	p.Glu19*	stop_gained	Exon 1 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.55G>T	p.Glu19*	stop_gained	Exon 1 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD2 exomes AF: 0.0000278 AC: 6 AN: 215878 AF XY: 0.0000167

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000692 AC: 10 AN: 1445022 Hom.: 0 Cov.: 74 AF XY: 0.00000279 AC XY: 2 AN XY: 717954

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.000206 AC: 9 AN: 43692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25806

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38984

South Asian (SAS) AF: 0.00 AC: 0 AN: 84754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105836

Other (OTH) AF: 0.00 AC: 0 AN: 59754

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000841 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4 Other:1

Dec 30, 2024

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.Glu19*) 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 (rs752514155, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233594). For these reasons, this variant has been classified as Pathogenic.

Mar 13, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 10, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BARD1 c.55G>T (p.Glu19X) 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 2.8e-05 in 215878 control chromosomes. To our knowledge, no occurrence of c.55G>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with other pathogenic variant has been reported (BRCA1 c.45delT, p.Asn16MetfsX7) at our laboratory. Six clinical diagnostic laboratories (Pathogenic n=5; VUS n=1) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 01-10-2022 by Invitae. GenomeConnect-InvitaePIN 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.

May 17, 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 termination codon and is predicted to result in premature protein truncation.

not provided Pathogenic:2

Jan 25, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BARD1 c.55G>T (p.Glu19*) variant causes the premature termination of BARD1 protein synthesis. This variant has not been reported in individuals with BARD1-related conditions in the published literature. However, this variant has been observed in an individual in our internal patient population with clinical features and family history consistent with disease associated with this gene. The frequency of this variant in the general population, 0.00021 (7/33694 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Dec 28, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32679805)

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E19* pathogenic mutation (also known as c.55G>T), located in coding exon 1 of the BARD1 gene, results from a G to T substitution at nucleotide position 55. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. 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.

Jun 03, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 1 of the BARD1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/247256 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	34
DANN	Benign	0.92
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.0	.;.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.
PhyloP100		-0.65
PROVEAN	Benign	0.0	.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.
Vest4		0.74
GERP RS		-8.0
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752514155; hg19: chr2-215674239;