7-55174773-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_005228.5(EGFR):c.2236G>C(p.Glu746Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E746K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.89

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain 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 chr7-55174773-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376276.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.2236G>C	p.Glu746Gln	missense_variant	19/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2236G>C	p.Glu746Gln	missense_variant	19/28	1	NM_005228.5	P1
EGFR	ENST00000455089.5	c.2101G>C	p.Glu701Gln	missense_variant	18/26	1
EGFR	ENST00000450046.2	c.2077G>C	p.Glu693Gln	missense_variant	19/28	4
EGFR	ENST00000700145.1	c.586G>C	p.Glu196Gln	missense_variant	6/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Non-small cell lung carcinoma Other:1

not provided, no classification provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 12, 2007

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.60	N;.;N
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.78	P;.;D
Vest4		0.68
MutPred		0.42		.;.;Gain of MoRF binding (P = 0.0917);
MVP		0.70
MPC		1.4
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913427; hg19: chr7-55242466;