chr2-214809568-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000465.4(BARD1):​c.2T>C​(p.Met1?) variant causes a start 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)

Consequence

BARD1
NM_000465.4 start_lost

Scores

6
2
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.27
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000465.4 (BARD1) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkc.2T>C p.Met1? start_lost 1/11 ENST00000260947.9 NP_000456.2 Q99728-1A0AVN2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkc.2T>C p.Met1? start_lost 1/111 NM_000465.4 ENSP00000260947.4 Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
73
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 11, 2019- -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 22, 2019This sequence change affects the initiator methionine of the BARD1 mRNA. However, another in-frame methionine that is highly conserved in mammals is located 25 codons downstream (p.Met26) and could potentially rescue the loss of initiator codon. In summary, this variant is a novel initiatior codon change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies have not been reported for this initiation codon variant and it is currently unknown if translation is rescued by either an in-frame or out-of-frame methionine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a BARD1-related disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.060
T;.;.;.;T;.;.
Eigen
Benign
0.13
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.55
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;.
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Benign
-0.33
T
PROVEAN
Benign
-0.52
N;.;.;.;.;.;N
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D;.;.;.;.;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Polyphen
0.90
P;.;.;.;.;.;.
Vest4
0.76
MutPred
0.98
Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);Gain of phosphorylation at M1 (P = 0.002);
MVP
0.94
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7
Varity_R
0.95
gMVP
0.47

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: rs1553628504; hg19: chr2-215674292; API