rs28929495

Positions:

• chr7-55174014-G-A
• chr7-55174014-G-C
• chr7-55174014-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_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. 12/21 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
• Clinical Significance: Uncertain significance; drug response criteria provided, multiple submitters, no conflicts P:2 U:1 O:3
• Conservation: PhyloP100: 9.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a binding_site (size 8) 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
EGFR	NM_005228.5	c.2155G>A	p.Gly719Ser	missense_variant	18/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2155G>A	p.Gly719Ser	missense_variant	18/28	1	NM_005228.5	P1
EGFR	ENST00000455089.5	c.2020G>A	p.Gly674Ser	missense_variant	17/26	1
EGFR	ENST00000450046.2	c.1996G>A	p.Gly666Ser	missense_variant	18/28	4
EGFR	ENST00000700145.1	c.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:2 Uncertain:1 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

-

- -

Non-small cell lung carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

EGFR-related lung cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2021

In 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 provided

literature only

OMIM

Jun 04, 2004

- -

Tyrosine kinase inhibitor response Other:1

drug response, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 20, 2012

- Responsive

Neoplasm of the large intestine Other:1

not provided, no classification provided

literature only

Database 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

Other links and lift over

dbSNP: rs28929495; hg19: chr7-55241707; COSMIC: COSV51767289; COSMIC: COSV51767289;