7-55163737-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_005228.5(EGFR):c.1636C>G(p.Pro546Ala) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P546S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-55163737-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376211.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.1636C>G	p.Pro546Ala	missense_variant	14/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.1636C>G	p.Pro546Ala	missense_variant	14/28	1	NM_005228.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EGFR-related lung cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 18, 2019

This sequence change replaces proline with alanine at codon 546 of the EGFR protein (p.Pro546Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with EGFR-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	0.0090	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Benign	0.31	T;.;T;.;D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.53	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;D;.;D;D;.
REVEL	Benign	0.19
Sift	Benign	0.23	T;T;.;T;T;.
Sift4G	Benign	0.50	T;D;T;D;T;.
Polyphen		0.095	B;D;.;D;B;.
Vest4		0.78
MutPred		0.42		.;Loss of disorder (P = 0.1318);.;Loss of disorder (P = 0.1318);Loss of disorder (P = 0.1318);.;
MVP		0.45
MPC		1.2
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.65
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1057519830; hg19: chr7-55231430;