2-214745752-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000465.4(BARD1):c.1780G>T(p.Ala594Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A594G) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
BARD1
NM_000465.4 missense
NM_000465.4 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 3.64
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 Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.1780G>T | p.Ala594Ser | missense_variant | 8/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1780G>T | p.Ala594Ser | missense_variant | 8/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461790Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727194
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 12, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 23, 2022 | The p.A594S variant (also known as c.1780G>T), located in coding exon 8 of the BARD1 gene, results from a G to T substitution at nucleotide position 1780. The alanine at codon 594 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 594 of the BARD1 protein (p.Ala594Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 406745). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;N
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;T
Sift4G
Benign
T;T;T;T;T
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of disorder (P = 0.0356);.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at