2-214781142-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000465.4(BARD1):​c.732C>G​(p.Ser244Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BARD1
NM_000465.4 missense

Scores

11
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31344762).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkuse as main transcriptc.732C>G p.Ser244Arg missense_variant 4/11 ENST00000260947.9 NP_000456.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.732C>G p.Ser244Arg missense_variant 4/111 NM_000465.4 ENSP00000260947 P2Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
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), LabcorpOct 18, 2023This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 244 of the BARD1 protein (p.Ser244Arg). 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. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Uncertain
0.015
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.77
T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Uncertain
-0.095
T
MutationAssessor
Uncertain
2.4
M;.
MutationTaster
Benign
0.77
D;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-2.3
N;.
REVEL
Benign
0.25
Sift
Uncertain
0.0050
D;.
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.89
P;.
Vest4
0.17
MutPred
0.45
Gain of catalytic residue at S244 (P = 0.0254);.;
MVP
0.92
MPC
0.35
ClinPred
0.90
D
GERP RS
3.9
Varity_R
0.16
gMVP
0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-215645866; API