rs879254139

Variant names:

• chr2-214797118-C-A
• rs879254139
• NM_000465.4:c.159-1G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-214797118-C-A
• chr2-214797118-C-G
• chr2-214797118-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PVS1_Moderate PP5_Very_Strong BS2

The NM_000465.4(BARD1):​c.159-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000685 in 1,459,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: BARD1 NM_000465.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 4.84
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024421593 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 2-214797118-C-A is Pathogenic according to our data. Variant chr2-214797118-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246176.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.159-1G>T		splice_acceptor_variant, intron_variant	Intron 1 of 10	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.159-1G>T		splice_acceptor_variant, intron_variant	Intron 1 of 10	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459560 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 726256

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1110100

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:6

May 18, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Nov 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 13, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 1 of the BARD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer, ovarian or prostate cancer (PMID: 31036035, 31843900). ClinVar contains an entry for this variant (Variation ID: 246176). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 31843900; internal data). For these reasons, this variant has been classified as Pathogenic. -

Dec 23, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -

not provided Pathogenic:4

May 04, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1 -

Feb 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to cause abnormal splicing producing multiple transcripts, the majority of which result in skipping of the adjacent exon(s), in a gene for which loss of function is a known mechanism of disease (PMID: 31843900); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31036035, 33804961, 33809641, 36747619, 35988656, 18480049, 31843900) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BARD1: PVS1:Strong, PM2, PS4:Moderate -

Jun 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BARD1 c.159-1G>T variant disrupts a canonical splice-acceptor site and interferes with normal BARD1 mRNA splicing. This variant has been reported in the published literature in affected individuals with breast cancer (PMIDs: 31036035 (2019) and 33471991 (2021)), ovarian and prostate cancer (PMID: 31843900 (2019)), b-cell neoplasms (PMID: 33809641 (2021)), as well as in a healthy individual (PMID: 33471991 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 09, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to T nucleotide substitution at the -1 position of intron 1 of the BARD1 gene. An RNA study has reported two aberrant transcripts found uniquely in carrier and absent in healthy control that are expected to produce absent or non-functional protein product (PMID: 31843900). This variant also has been reported in one individual each affected with breast and ovarian cancer (PMID: 31036035, 31843900). This variant has not been identified 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. -

Aug 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.159-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 2 of the BARD1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). A published RNA study also identified abnormal splicing associated with this variant (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). In one study, this alteration was detected in 1/4469 German breast cancer patients (Weber-Lassalle N et al. Breast Cancer Res., 2019 04;21:55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jul 09, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (strong pathogenic): Transcript ENST00000260947 does not undergo NMD and reading frame is preserved. Skipped exon is considered disease relevant region.Truncated exon overlaps the following clinically significant domains: RING in BARD1. ENST00000619009: PVS1 strong applies: Transcript ENST00000619009 does not undergo NMD and reading frame is preserved. Skipped exon is considered disease relevant region.Truncated exon overlaps the following clinically significant domains: RING in BARD1. ENST00000613706: PVS1 strong applies: Transcript ENST00000613706 does not undergo NMD and reading frame is preserved. Skipped exon is considered disease relevant region.Truncated exon overlaps the following clinically significant domains: RING in BARD1. ENST00000421162: PVS1 strong applies: Transcript ENST00000421162 does not undergo NMD and reading frame is preserved. Skipped exon is considered disease relevant region.Truncated exon overlaps the following clinically significant domains: RING in BARD1. ENST00000620057: PVS1 strong applies: Transcript ENST00000620057 does not undergo NMD and reading frame is preserved. Skipped exon is considered disease relevant region.Truncated exon overlaps the following clinically significant domains: RING in BARD1. ENST00000455743: PVS1 strong applies: Transcript ENST00000455743 does not undergo NMD and reading frame is preserved. Skipped exon is considered disease relevant region.Truncated exon overlaps the following clinically significant domains: RING in BARD1. , PS4 (supporting pathogenic): 5X in GC-HBOC in BRIDGES 1X in 53.000 controls and 3X in 60466 BC cases, PM2 (supporting pathogenic): Variant is absent from gnomAD.; Based on evidence we decided that these criteria can not be selected: BP3 (supporting benign): Transcript ENST00000260947 does not carry variant of exonic or intronic variant type. ENST00000619009: BP3 does not applies: Transcript ENST00000619009 does not carry variant of exonic or intronic variant type. ENST00000613706: BP3 does not applies: Transcript ENST00000613706 does not carry variant of exonic or intronic variant type. ENST00000421162: BP3 does not applies: Transcript ENST00000421162 does not carry variant of exonic or intronic variant type. ENST00000620057: BP3 does not applies: Transcript ENST00000620057 does not carry variant of exonic or intronic variant type. ENST00000455743: BP3 does not applies: Transcript ENST00000455743 does not carry variant of exonic or intronic variant type. , BP4 (supporting benign): Variant is not predicted to have no splicing effect by SpliceAI., BP7 (supporting benign): BP7 does not apply to this variant, as BP7 does not apply to variant types upstream_gene_variant, non_coding_transcript_variant, nmd_transcript_variant, intron_variant, splice_acceptor_variant., BS1 (strong benign): Variant does not occur in gnomAD, allele frequency in gnomAD is assumed to be 0., BA1 (stand-alone benign): Variant occures with 0 in gnomAD subpopulation None. -

Feb 07, 2017

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: The BARD1 c.159-1G>T variant involves the alteration of a conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant. 4/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121314 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.8
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
Splicevardb		3.0
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs879254139; hg19: chr2-215661842;