chr2-214728677-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_000465.4(BARD1):​c.2333G>C​(p.Ter778SerextTer10) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. *778*) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BARD1
NM_000465.4 stop_lost

Scores

2
1
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.33
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Stoplost variant in NM_000465.4 Downstream stopcodon found after 110 codons.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BARD1NM_000465.4 linkuse as main transcriptc.2333G>C p.Ter778SerextTer10 stop_lost 11/11 ENST00000260947.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.2333G>C p.Ter778SerextTer10 stop_lost 11/111 NM_000465.4 P2Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 01, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 13, 2021The c.2333G>C variant (also known as p.*778Sext*10), located in coding exon 11 of the BARD1 gene, results from a G to C substitution at nucleotide position 2333.This alteration disrupts the stop codon of the BARD1 gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 10 amino acids. The exact functional effect of the additional amino acids is unknown. 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 submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterSep 13, 2023This sequence change disrupts the translational stop signal of the BARD1 mRNA. It is expected to extend the length of the BARD1 protein by 10 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). The exact functional effect of the additional amino acids is unknown. 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: 628819) classified as uncertain significant . 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 26, 2023In 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. ClinVar contains an entry for this variant (Variation ID: 628819). 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 disrupts the translational stop signal of the BARD1 mRNA. It is expected to extend the length of the BARD1 protein by 10 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
13
DANN
Benign
0.82
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
N;N
Vest4
0.34
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs776958611; hg19: chr2-215593401; API