rs187240320
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000465.4(BARD1):c.2002-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000089 ( 1 hom. )
Consequence
BARD1
NM_000465.4 splice_polypyrimidine_tract, intron
NM_000465.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00002390
2
Clinical Significance
Conservation
PhyloP100: -0.0250
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
?
Variant 2-214729019-G-A is Benign according to our data. Variant chr2-214729019-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 182031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000105 (16/152256) while in subpopulation EAS AF= 0.00231 (12/5192). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.2002-11C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.2002-11C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000141 AC: 35AN: 249064Hom.: 0 AF XY: 0.000141 AC XY: 19AN XY: 134706
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GnomAD4 exome AF: 0.0000890 AC: 130AN: 1460866Hom.: 1 Cov.: 31 AF XY: 0.0000702 AC XY: 51AN XY: 726750
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Dec 01, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 03, 2021 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 29, 2023 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 c.2002-11C>T variant was not identified in the literature nor was it identified in the Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs187240320) as “With Likely benign allele”, ClinVar (as benign by GeneDx and likely benign by University of Washington Dept. of Laboratory Medicine), and Clinvitae databases. The variant was identified in control databases in 39 of 274896 chromosomes at a frequency of 0.000142 (Genome Aggregation Database Feb 27, 2017). Observation by population include: “Other” in 1 of 6430 chromosomes (freq: 0.000156), East Asian in 36 of 18830 chromosomes (freq: 0.001912), and South Asian in 2 of 30680 chromosomes (freq: 0.000065); the variant was not observed in the African, Latino, European (Non-Finnish), Ashkenazi Jewish, or European (Finnish) populations. The c.2002-11C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was identified by our laboratory co-occurring with a pathogenic BRCA1 variant (c.5503C>T), increasing the likelihood that the c.2002-11C>T variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at