chr7-55173985-A-C

Position:

• chr7-55173985-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005228.5(EGFR):​c.2126A>C​(p.Glu709Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E709K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 9.23

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2126A>C	p.Glu709Ala	missense_variant	18/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2126A>C	p.Glu709Ala	missense_variant	18/28	1	NM_005228.5	ENSP00000275493	P1
EGFR	ENST00000455089.5	c.1991A>C	p.Glu664Ala	missense_variant	17/26	1		ENSP00000415559
EGFR	ENST00000450046.2	c.1967A>C	p.Glu656Ala	missense_variant	18/28	4		ENSP00000413354
EGFR	ENST00000700145.1	c.476A>C	p.Glu159Ala	missense_variant	5/9			ENSP00000514824

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, single submitter

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

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 05, 2012

- -

Lung carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Jun 27, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.9	.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.2	D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.93	P;.;D
Vest4		0.84
MutPred		0.44		.;.;Gain of MoRF binding (P = 0.0354);
MVP		0.79
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.73

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

Other links and lift over

dbSNP: rs397517085; hg19: chr7-55241678; COSMIC: COSV51772956; COSMIC: COSV51772956;