rs1057519890
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_004448.4(ERBB2):c.2263T>A(p.Leu755Met) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: not found (cov: 31)
Consequence
ERBB2
NM_004448.4 missense
NM_004448.4 missense
Scores
3
14
2
Clinical Significance
Conservation
PhyloP100: 3.44
Genes affected
ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]
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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;
PP2
Missense variant in the ERBB2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 3.2497 (above the threshold of 3.09). Trascript score misZ: 4.234 (above the threshold of 3.09). GenCC associations: The gene is linked to visceral neuropathy, familial, 2, autosomal recessive, lung cancer, Hirschsprung disease, glioma susceptibility 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.769
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:7
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Papillary renal cell carcinoma, sporadic Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Malignant neoplasm of body of uterus Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Gastric adenocarcinoma Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Breast neoplasm Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Transitional cell carcinoma of the bladder Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Malignant melanoma of skin Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Neoplasm of the large intestine Pathogenic:1
May 31, 2016
Database of Curated Mutations (DoCM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;D;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;.;.;.;.;M
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;N;N;.;N
REVEL
Uncertain
Sift
Uncertain
.;D;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;.;D
Vest4
MutPred
0.81
.;.;.;.;Gain of disorder (P = 0.0772);Gain of disorder (P = 0.0772);
MVP
MPC
2.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at