2-214767486-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000465.4(BARD1):​c.1564G>A​(p.Ala522Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,950 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. A522S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.34
Variant links:
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BARD1NM_000465.4 linkc.1564G>A p.Ala522Thr missense_variant Exon 6 of 11 ENST00000260947.9 NP_000456.2 Q99728-1A0AVN2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkc.1564G>A p.Ala522Thr missense_variant Exon 6 of 11 1 NM_000465.4 ENSP00000260947.4 Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1460950
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
726842
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 18, 2016
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is denoted BARD1 c.1564G>A at the cDNA level, p.Ala522Thr (A522T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Ala522Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Ala522Thr occurs at a position where amino acids with properties similar to Alanine are tolerated across species, and it is located in the ANK3 repeat domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BARD1 Ala522Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Familial cancer of breast Uncertain:1
Aug 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 182048). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 522 of the BARD1 protein (p.Ala522Thr). -

Hereditary cancer-predisposing syndrome Uncertain:1
Apr 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.A522T variant (also known as c.1564G>A), located in coding exon 6 of the BARD1 gene, results from a G to A substitution at nucleotide position 1564. The alanine at codon 522 is replaced by threonine, an amino acid with similar properties. This amino acid position is not 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.064
T;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.023
T
MetaRNN
Uncertain
0.56
D;D
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.4
N;.
REVEL
Uncertain
0.29
Sift
Benign
0.16
T;.
Sift4G
Benign
0.17
T;T
Polyphen
0.97
D;.
Vest4
0.52
MutPred
0.61
Loss of methylation at R520 (P = 0.1391);.;
MVP
0.92
MPC
0.42
ClinPred
0.88
D
GERP RS
5.6
Varity_R
0.34
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730881419; hg19: chr2-215632210; API