rs769696078

Variant names:

• chr7-55154128-G-A
• rs769696078
• NM_005228.5:c.865G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005228.5(EGFR):​c.865G>A​(p.Ala289Thr) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 8.09

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.865G>A	p.Ala289Thr	missense_variant	Exon 7 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.865G>A	p.Ala289Thr	missense_variant	Exon 7 of 28	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

EGFR-related lung cancer Uncertain:1

Sep 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EGFR protein function. ClinVar contains an entry for this variant (Variation ID: 376395). This variant has not been reported in the literature in individuals affected with EGFR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 289 of the EGFR protein (p.Ala289Thr). -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;.;D;.;.;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Pathogenic	3.0	.;M;.;M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D;D;.;D;D;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;D;.;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;.
Polyphen		0.98	D;D;.;D;D;D;.
Vest4		0.82
MutPred		0.86		.;Gain of disorder (P = 0.1258);.;Gain of disorder (P = 0.1258);Gain of disorder (P = 0.1258);Gain of disorder (P = 0.1258);.;
MVP		0.81
MPC		1.4
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.86
gMVP		0.68

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: rs769696078; hg19: chr7-55221821; COSMIC: COSV51770322;