chr2-214797118-C-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong
The NM_000465.4(BARD1):c.159-1G>T variant causes a splice acceptor 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
NM_000465.4 splice_acceptor
Scores
4
2
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.84
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.023993146 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.159-1G>T | splice_acceptor_variant | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.159-1G>T | splice_acceptor_variant | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1459560Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8AN XY: 726256
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29
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8
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | 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; Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 13, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 18, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 23, 2022 | _x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 24, 2021 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 14, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | BARD1: PVS1, PM2 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | May 04, 2022 | PVS1 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2022 | Canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: abnormal splicing (Casadei et al., 2019); This variant is associated with the following publications: (PMID: 31843900, 31036035, 33804961, 33809641) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 09, 2021 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2023 | 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. 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 was not reported in population-based 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 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). 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2017 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at