rs587781948

Variant names:

• chr2-214730491-G-A
• rs587781948
• NM_000465.4:c.1921C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-214730491-G-A
• chr2-214730491-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_000465.4(BARD1):​c.1921C>T​(p.Arg641*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,374 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R641R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: BARD1 NM_000465.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 3.31
• Publications: 29 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]

BARD1 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-214730491-G-A is Pathogenic according to our data. Variant chr2-214730491-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 141702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1921C>T	p.Arg641*	stop_gained	Exon 10 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1921C>T	p.Arg641*	stop_gained	Exon 10 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251290 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461396 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727000

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111644

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74222

African (AFR) AF: 0.0000484 AC: 2 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00000931 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2025

GeneDx

Significance: 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); This variant is associated with the following publications: (PMID: 26010302, 26483394, 26315354, 28174632, 28050010, 23334666, 29292755, 28055978, 28724667, 27009842, 32832836, 32566746, 33498765, 32427313, 32679805, 35892882, 36187937, 35353237, 36243179, 36493725, 34326862, 37688579, 32980694, 29922827, 37762649) -

Jul 10, 2023

Revvity Omics, Revvity

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

- -

Mar 28, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of BARD1 protein synthesis. In addition, it has been reported in multiple individuals and families affected with various cancers including breast cancer, pancreatic cancer, prostate cancer, and neuroblastoma in the published literature (PMID: 23334666 (2013), 26483394 (2015), 26010302 (2016), 28724667 (2017), 28174632 (2017), 28050010 (2017), 32566746 (2020), 32832836 (2020)). Based on the available information, this variant is classified as pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Feb 21, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R641* pathogenic mutation (also known as c.1921C>T), located in coding exon 10 of the BARD1 gene, results from a C to T substitution at nucleotide position 1921. This changes the amino acid from an arginine to a stop codon within coding exon 10. This pathogenic mutation has been reported in several individuals diagnosed with breast cancer (De Brakeleer S et al. Clin. Genet. 2016 Mar;89:336-40; Feliubadaló L et al. Sci Rep, 2017 01;7:37984; Gass J et al. Clin Case Rep. 2017 Feb;5:104-107; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Kaneyasu T et al. NPJ Breast Cancer, 2020 Jun;6:25; Rofes P et al. Genes (Basel), 2021 01;12:). It has also been reported in individuals with neuroblastoma and pancreatic cancer (Pugh TJ et al. Nat. Genet. 2013 Mar;45:279-84; Lasorsa VA et al. Oncotarget, 2016 Apr;7:21840-52; Hu C et al. Cancer Epidemiol Biomarkers Prev, 2016 Jan;25:207-11). 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. -

Oct 29, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 13, 2022

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 10 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 individuals affected with breast cancer, pancreatic cancer, or neuroblastoma (PMID: 23334666, 26010302, 26483394, 28174632, 28724667, 32566746, 33471991, 33498765). This variant has been identified in 5/282680 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. -

Mar 20, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4_Supporting c.1921C>T, located in exon 10 of the BARD1 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1). This variant is found in 5/268150 alleles at a frequency of 0,001% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. To our knowledge, no well-established functional studies have been reported for this variant. It has been reported in two case-control studies, being found in 4 out of 60466 and 1 out of 38 breast cancer-affected patients and none of the 53461 and 245 healthy controls, respectively (PMID:33471991, PMID: 26010302). This variant has been found in multiple cancer-affected individuals without BRCA1/2 pathogenic variants (PMID: 26483394, PMID: 33498765, PMID: 28050010, PMID: 28174632, and data from our internal cohort) (PS4_Supporting). This variant cosegregates with the disease in multiple individuals from our internal cohort of patients. This variant has been reported in the ClinVar database (17x pathogenic), and in the LOVD (1x pathogenic) Based on currently available information, the variant c.1921C>T should be considered a likely pathogenic variant according to ACMG/AMP classification guidelines. -

Familial cancer of breast Pathogenic:3

Jan 29, 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.Arg641*) 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 (rs587781948, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuroblastoma, pancreatic cancer, and breast cancer (PMID: 23334666, 26010302, 26483394, 28174632). ClinVar contains an entry for this variant (Variation ID: 141702). For these reasons, this variant has been classified as Pathogenic. -

Nov 19, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Hereditary breast ovarian cancer syndrome Pathogenic:2

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 28, 2019

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.1921C>T (p.Arg641X) 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 1.8e-05 in 282680 control chromosomes (gnomAD). c.1921C>T has been reported in the literature in multiple individuals affected with breast- and pancreatic cancer (e.g. DeBrakeleer_2016, Hu_2016, Feliubadalo_2017, Gas_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

BARD1-related cancer predisposition Pathogenic:1

Aug 19, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Triple-Negative Breast Cancer Finding Pathogenic:1

Feb 01, 2015

Lab. Molecular Oncology, VUB, Free University of Brussels

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BARD1 p.Arg641* variant was identified in 3 of 712 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer, pancreatic cancer and neuroblastoma (Pugh 2013, Hu 2016, De Brakeleer 2016). The variant was also identified in dbSNP (ID: rs587781948) as "With Pathogenic allele", ClinVar (3x pathogenic: Ambry genetics, Invitae, GeneDx), Clinvitae (3x pathogenic: Ambry genetics, Invitae, GeneDx), databases. The variant was not identified in COSMIC, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 5 of 277022 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This mutation is expected to result in either nonsense mediated mRNA decay or, if translated, truncation of the protein product and absence of the last BRCA1 carboxy-terminal (BRCT) domain of the BARD1 protein. Loss of function variants of the BARD1 gene are an established mechanism of disease in breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		3.3
Vest4		0.93
GERP RS		3.9
PromoterAI		-0.030	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587781948; hg19: chr2-215595215;