2-214780559-C-T

Variant names:

• chr2-214780559-C-T
• rs753785671
• NM_000465.4:c.1314+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000465.4(BARD1):​c.1314+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000205 in 1,460,632 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BARD1 NM_000465.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.14
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-214780559-C-T is Pathogenic according to our data. Variant chr2-214780559-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 479152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.1314+1G>A		splice_donor intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.1257+1G>A		splice_donor intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.215+16502G>A		intron	N/A	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.1314+1G>A		splice_donor intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.1257+1G>A		splice_donor intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.906+409G>A		intron	N/A	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250606 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460632 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726706

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60338

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

May 22, 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.

Dec 12, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 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 present in population databases (rs753785671, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuroblastoma or personal and/or family history of breast and/or ovarian cancer (PMID: 27009842, 29752822, 33498765). ClinVar contains an entry for this variant (Variation ID: 479152). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

not provided Pathogenic:2

May 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BARD1 c.1314+1G>A variant disrupts a canonical splice-donor site, and has been described to cause out-of-frame exon skipping based on RNA analysis (PMID: 33498765 (2021)). This variant has been reported in individuals with breast cancer (PMID: 29752822 (2018)), ovarian cancer (PMID: 33498765 (2021)), and neuroblastoma (PMID: 27009842 (2016)). The frequency of this variant in the general population, 0.000004 (1/250606 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Jun 09, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 12, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1314+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the BARD1 gene. This variant was identified in 1/937 Chinese breast cancer patients undergoing multigene panel testing (Li JY et al. Int J Cancer, 2019 01;144:281-289). This variant was also detected in a women with ovarian cancer that was part of a Spanish cohort of 4015 index patients with a personal or family history suggestive of hereditary breast and/or ovarian cancer (Rofes P et al. Genes (Basel), 2021 Jan;12). 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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

Apr 09, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_RNA, PM2_Supporting c.1314+1G>A, located in a canonic splicing site of the BARD1 is predicted to alter splicing. RNA studies have shown that this variant causes skipping of exons 3 and 4 (r.216_1314del; p.Ser72Argfs*37) and it results in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1_RNA) (PMID: 33498765). This variant is found in 1/267513 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset (PM2_supporting). It has been reported in ClinVar (1x P, 5x LP). This variant has been reported in the ClinVar database (5x likely pathogenic, 1x pathogenic). Based on the currently available information, c.1314+1G>A is classified as a likely pathogenic variant according to ACMG guidelines.

BARD1-related cancer predisposition Pathogenic:1

Jun 18, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Pathogenic:1

Nov 14, 2024

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.1314+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of BARD1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a cryptic 3' acceptor site. One predict the variant creates a 3' acceptor site. The variant allele was found at a frequency of 4e-06 in 250606 control chromosomes. c.1314+1G>A has been reported in the literature in individuals with a personal or family history of Hereditary Breast And Ovarian Cancer Syndrome (Feliubadalo_2019, Li_2019, Rofes_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 30927264, 29752822, 33498765). ClinVar contains an entry for this variant (Variation ID: 479152). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		5.1
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 1

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

Other links and lift over

dbSNP: rs753785671; hg19: chr2-215645283;