7-55191822-T-G

Variant names:

• chr7-55191822-T-G
• rs121434568
• NM_005228.5:c.2573T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005228.5(EGFR):​c.2573T>G​(p.Leu858Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L858M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: drug response reviewed by expert panel P:3 U:1 O:8
• Conservation: PhyloP100: 7.96
• Publications: 10438 publications found

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]

EGFR-AS1 (HGNC:40207): (EGFR antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_005228.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2573T>G	p.Leu858Arg	missense_variant	Exon 21 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2573T>G	p.Leu858Arg	missense_variant	Exon 21 of 28	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: drug response

Submissions summary: Pathogenic:3 Uncertain:1 Other:8

Revision: reviewed by expert panel

Submissions by phenotype

Non-small cell lung carcinoma Other:3

Feb 23, 2018

CIViC knowledgebase, Washington University School of Medicine

Significance:

Review Status: criteria provided, single submitter

Collection Method: curation

L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor erlotinib is associated with improved progression free survival over chemotherapy in EGFR L858R patients (civic.EID:885).

Feb 22, 2018

CIViC knowledgebase, Washington University School of Medicine

Significance:

Review Status: criteria provided, single submitter

Collection Method: curation

L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis, including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor afatinib is FDA approved as a first line systemic therapy in NSCLC with sensitizing EGFR mutation (civic.EID:2997).

Feb 23, 2018

Wagner Lab, Nationwide Children's Hospital

Significance:

Review Status: criteria provided, single submitter

Collection Method: curation

L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor erlotinib is associated with improved progression free survival over chemotherapy in EGFR L858R patients (civic.EID:885).

Lung adenocarcinoma Pathogenic:2

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 06, 2022

Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Lung carcinoma Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L858R variant (also known as c.2573T>G), located in coding exon 21 of the EGFR gene, results from a T to G substitution at nucleotide position 2573. The leucine at codon 858 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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

Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in, somatic Other:1

May 19, 2005

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

Tyrosine kinase inhibitor response Other:1

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: clinical testing

Responsive

gefitinib response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Adenocarcinoma of lung, response to tyrosine kinase inhibitor in, somatic Other:1

May 19, 2005

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.0	.;.;H
PhyloP100		8.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.2	D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.99
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434568; hg19: chr7-55259515; COSMIC: COSV51765161; COSMIC: COSV51765161;