rs121434569

Positions:

chr7-55181378-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP3_StrongPP5_Strong

The NM_005228.5(EGFR):c.2369C>T(p.Thr790Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T790S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

EGFR
NM_005228.5 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:9B:1O:4

Conservation

PhyloP100: 4.95

Variant links:

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 links:

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

EGFR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a domain Protein kinase (size 267) in uniprot entity EGFR_HUMAN there are 56 pathogenic changes around while only 8 benign (88%) in NM_005228.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 7-55181378-C-T is Pathogenic according to our data. Variant chr7-55181378-C-T is described in ClinVar as [drug_response]. Clinvar id is 16613.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, drug_response=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.2369C>T	p.Thr790Met	missense_variant	20/28	ENST00000275493.7
EGFR-AS1	NR_047551.1 linkuse as main transcript	n.1193G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.2369C>T	p.Thr790Met	missense_variant	20/28	1	NM_005228.5	P1	P00533-1
EGFR-AS1	ENST00000442411.2 linkuse as main transcript	n.1221G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251464

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: drug response

Submissions summary: Pathogenic:9Benign:1Other:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Non-small cell lung carcinoma

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Mar 10, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 11, 2014	The p.Thr790Met variant in EGFR has been identified as a somatic change in individuals with non-small cell lung cancer (NSCLC) that have an acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs), often in combination with other EGFR kinase domain mutations (Pao 2005). In addition, this variant has been identified as a germline mutation in at least 14 unrelated individuals with NSCLC (including never smokers; Bell 2005, Prudkin 2009, Girard 2010, Tibaldi 2011, Oxnard 2012, Thomas 2013, Gazdar 2014, Yu 2014) and segregated with lung cancer and pulmonary disease in at least 4 affected individuals from 3 families (Bell 2005, Gazdar 2012, Yu 2014). This variant was absent from large population studies. While the literature reports strongly suggest that the p.Thr790Met variant can predispose to lung cancer, the penetrance of a germline p.Thr790Met variant has not been established and the functional impact of this variant in the germline is not well understood. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

Tyrosine kinase inhibitor response

Other:2

drug response, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 11, 2014	The Thr790Met variant in EGFR has been identified as a somatic change in individuals with non-small cell lung cancer (NSCLC) that have an acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs), often in combination with other EGFR kinase domain mutations (Pao 2005). This variant has been found to arise in 60% of patients with acquired resistance to TKIs. In summary, the Thr790Met variant meets our criteria to be classified as resistant (http://pcpgm.partners.org/LMM). Resistant
drug response, no assertion criteria provided	research	Institute of Medical Sciences, Banaras Hindu University	Oct 30, 2020	- Likely responsive

Lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2020

In summary, in vivo experiments demonstrated that T790M drives lung adenocarcinomas and is required for tumor maintenance (Regales et al., 2007); In vitro experiments demonstrated that T790M activated EGFR signaling pathway and provided a growth advantage for cancer cells (Viskis et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33504652, 29625052, 30610926, 30225213, 28989039, 23817662, 24736066, 24736080, 24453288, 11423618, 22426079, 26700910, 28125075, 28843361, 28982744, 28947568, 23540867, 19096324, 16258541, 22588155, 20068085, 24478319, 17726540, 18227510, 17510392, 15728811, 18632637, 24053674, 15737014, 27251290, 15272417, 20033049, 21252721, 26799287, 27734950) -

EGFR-related lung cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 790 of the EGFR protein (p.Thr790Met). This variant is present in population databases (rs121434569, gnomAD 0.02%). This missense change has been observed in individual(s) with lung cancer and pulmonary disease, many of whom were never smokers. In a study estimating the disease penetrance of this variant, individuals who carried the variant had a 15-31% overall risk for developing lung cancer. However, these data should be further validated in studies with larger sample (PMID: 16258541, 21252721, 23540867, 24736066, 24736080, 26700910). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16613). 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 expected to disrupt EGFR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EGFR function (PMID: 15728811, 15737014, 17510392, 17726540, 18227510). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2023

The p.T790M variant (also known as c.2369C>T), located in coding exon 20 of the EGFR gene, results from a C to T substitution at nucleotide position 2369. The threonine at codon 790 is replaced by methionine, an amino acid with similar properties. This alteration is a well known somatic alteration that is acquired and confers resistance to tyrosine kinase inhibitors which are agents used to treat lung cancer (Pao W et al. PLoS Med., 2005 Mar;2:e73). However, it has also been identified in the germline of many individuals with a personal and/or family history of lung cancer and segregates with lung cancer in some of these families, including in people who are considered never-smokers (Bell DW et al. Nat. Genet. 2005 Dec;37:1315-6; Prudkin L et al. J Thorac Oncol, 2009 Jan;4:139-41; Girard N et al. Clin. Cancer Res., 2010 Jan;16:755-63; Tibaldi C et al. J Thorac Oncol. 2011 Feb;6:395-6; Oxnard GR et al. J Thorac Oncol, 2012 Jun;7:1049-52; Thomas A et al. Clin Lung Cancer, 2013 Jul;14:452-6; Gazdar A et al. J Thorac Oncol. 2014 Apr;9:456-63; Yu HA et al. J Thorac Oncol. 2014 Apr;9:554-8; Lou Y et al. Clin Lung Cancer, 2016 Mar;17:e5-11; Hu Y et al. Clin. Cancer Res., 2017 Dec;23:7351-7359; Huang KL et al. Cell 2018 04;173(2):355-370.e14; Lu S et al. J Thorac Oncol. 2019 04;14:732-736; Reckamp KL et al. Cancer, 2021 Aug;127:2801-2806). Functional studies have shown that this alteration precludes binding of some TKIs, but that it also increases the binding affinity of EGFR for ATP which would lead to increased activation of the protein and increased cell growth (Pao W et al. PLoS Med., 2005 Mar;2:e73; Kobayashi S et al. N. Engl. J. Med., 2005 Feb;352:786-92; Regales L et al. PLoS ONE, 2007 Aug;2:e810; Yun CH et al. Proc. Natl. Acad. Sci. U.S.A., 2008 Feb;105:2070-5; Vikis H et al. Cancer Res., 2007 May;67:4665-70). Mice expressing an inducible transgene carrying this alteration develop lung adenocarcinomas, and this alteration is required for them to maintain their tumors (Regales L et al. PLoS ONE, 2007 Aug;2:e810). This alteration has a preliminary risk estimate of 31% in never smokers (Gazdar A et al. J Thorac Oncol, 2014 Apr;9:456-63). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Lung cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant p.T790M in EGFR (NM_005228.5) has been reported in multiple patients with adenocarcinoma of lung. In majority of the cases the mutation has been detected by somatic testing. Germline mutation T790M has been reported in a subset of patients both with and without disease implying incomplete penetrance (Helena Yu A et al, 2014; Gazdar A et al, 2014; Oxnard GR et al, 2012; Tibaldi C et al, 2011). The variant has been classified by the expert review panel in Clin Var as Pathogenic with respect to drug response. It is present in 10 alleles in heterozygote state (0.003%) in the gnomAD database. There is a moderate physicochemical difference between threonine and methionine. The p.T790M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.2369 in EGFR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Inflammatory skin and bowel disease, neonatal, 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 07, 2023

- -

Nonsmall cell lung cancer, resistance to tyrosine kinase inhibitor in

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Dec 24, 2009

- -

erlotinib response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

gefitinib response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;D;D

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Benign

-0.47

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0030

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.95

MutPred

0.91

.;.;Loss of catalytic residue at T790 (P = 0.0799);

MVP

0.90

MPC

1.5

ClinPred

0.76

GERP RS

5.9

Varity_R

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over