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rs28929495

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_005228.5(EGFR):c.2155G>A(p.Gly719Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G719C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

EGFR
NM_005228.5 missense

Scores

12
5
1

Clinical Significance

Uncertain significance; drug response criteria provided, multiple submitters, no conflicts P:2U:1O:3

Conservation

PhyloP100: 9.90
Variant links:
Genes affected
EGFR (HGNC:3236): (epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a strand (size 9) in uniprot entity EGFR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005228.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-55174015-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 45225.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFRNM_005228.5 linkuse as main transcriptc.2155G>A p.Gly719Ser missense_variant 18/28 ENST00000275493.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFRENST00000275493.7 linkuse as main transcriptc.2155G>A p.Gly719Ser missense_variant 18/281 NM_005228.5 P1P00533-1
EGFRENST00000455089.5 linkuse as main transcriptc.2020G>A p.Gly674Ser missense_variant 17/261
EGFRENST00000450046.2 linkuse as main transcriptc.1996G>A p.Gly666Ser missense_variant 18/284
EGFRENST00000700145.1 linkuse as main transcriptc.505G>A p.Gly169Ser missense_variant 5/9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance; drug response
Submissions summary: Pathogenic:2Uncertain:1Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingKey Laboratory of Carcinogenesis and Cancer Invasion, Central South University-- -
Non-small cell lung carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -
EGFR-related lung cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeFeb 20, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in germline 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is a common somatic change in non-small cell lung cancer (NSCLC) (PMID: 29100434, 25061320, 23468066, 24039832). While this variant has been reported in the literature, it has not been reported in the germline of individuals with EGFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 16612). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 719 of the EGFR protein (p.Gly719Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -
Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in, somatic Other:1
drug response, no assertion criteria providedliterature onlyOMIMJun 04, 2004- -
Tyrosine kinase inhibitor response Other:1
drug response, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 20, 2012- Responsive
Neoplasm of the large intestine Other:1
not provided, no classification providedliterature onlyDatabase of Curated Mutations (DoCM)Mar 10, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.36
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;D;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Uncertain
0.77
D
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-5.1
D;.;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0030
D;.;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.94
MutPred
0.95
.;.;Gain of phosphorylation at G719 (P = 0.1215);
MVP
0.94
MPC
1.4
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs28929495; hg19: chr7-55241707; COSMIC: COSV51767289; COSMIC: COSV51767289; API