chr2-214728681-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000465.4(BARD1):​c.2329A>C​(p.Ser777Arg) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BARD1
NM_000465.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.50
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.112570494).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkuse as main transcriptc.2329A>C p.Ser777Arg missense_variant 11/11 ENST00000260947.9 NP_000456.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.2329A>C p.Ser777Arg missense_variant 11/111 NM_000465.4 ENSP00000260947 P2Q99728-1

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 03, 2018In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BARD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 777 of the BARD1 protein (p.Ser777Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.051
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;.;.;.;T;.
Eigen
Benign
-0.082
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;.
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.11
T;T;T;T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
1.4
L;.;.;.;.;.
MutationTaster
Benign
0.96
N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.1
N;.;.;.;.;.
REVEL
Benign
0.042
Sift
Uncertain
0.0060
D;.;.;.;.;.
Sift4G
Uncertain
0.0050
D;D;D;D;D;D
Polyphen
0.036
B;.;.;.;.;.
Vest4
0.13
MutPred
0.21
Gain of solvent accessibility (P = 0.0155);.;.;.;.;.;
MVP
0.86
MPC
0.10
ClinPred
0.54
D
GERP RS
5.6
Varity_R
0.18
gMVP
0.37

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: rs1553611997; hg19: chr2-215593405; API