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rs121434569

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

9
6
3

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

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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: {Pathogenic=2, Likely_pathogenic=3, drug_response=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFRNM_005228.5 linkuse as main transcriptc.2369C>T p.Thr790Met missense_variant 20/28 ENST00000275493.7
EGFR-AS1NR_047551.1 linkuse as main transcriptn.1193G>A non_coding_transcript_exon_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFRENST00000275493.7 linkuse as main transcriptc.2369C>T p.Thr790Met missense_variant 20/281 NM_005228.5 P1P00533-1
EGFR-AS1ENST00000442411.2 linkuse as main transcriptn.1221G>A non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152222
Hom.:
0
Cov.:
33
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:
7
AN:
251464
Hom.:
0
AF XY:
0.0000147
AC XY:
2
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:
9
AN:
1461878
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
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:
7
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
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.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000412
AC:
5
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 providedliterature onlyDatabase of Curated Mutations (DoCM)Mar 10, 2016- -
Likely pathogenic, no assertion criteria providedclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 11, 2014The 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 providedresearchInstitute of Medical Sciences, Banaras Hindu UniversityOct 30, 2020- Likely responsive
drug response, no assertion criteria providedclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 11, 2014The 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
Lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingKey Laboratory of Carcinogenesis and Cancer Invasion, Central South University-- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxSep 08, 2020In 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 submitterclinical testingInvitaeJan 31, 2024This 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 submitterclinical testingAmbry GeneticsJul 18, 2023The 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 submitterclinical testingNeuberg 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 submitterclinical testingBaylor GeneticsSep 29, 2023- -
Nonsmall cell lung cancer, resistance to tyrosine kinase inhibitor in Benign:1
protective, no assertion criteria providedliterature onlyOMIMDec 24, 2009- -
erlotinib response - Efficacy Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.18
Cadd
Pathogenic
28
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
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Benign
0.065
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Benign
-0.47
T
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.77
T
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
D
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.

Other links and lift over

dbSNP: rs121434569; hg19: chr7-55249071; COSMIC: COSV51765492; API