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NM_005228.5(EGFR):c.2369C>T (p.Thr790Met)

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Interpretation:
drug response​

Review status:
reviewed by expert panel
Submissions:
8 (Most recent: Mar 28, 2019)
Last evaluated:
Jun 23, 2016
Accession:
VCV000016613.3
Variation ID:
16613
Description:
single nucleotide variant
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NM_005228.5(EGFR):c.2369C>T (p.Thr790Met)

Allele ID
31652
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7p11.2
Genomic location
7: 55181378 (GRCh38) GRCh38 UCSC
7: 55249071 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.14:g.55181378C>T
NC_000007.13:g.55249071C>T
LRG_304t1:c.2369C>T LRG_304p1:p.Thr790Met
... more HGVS
Protein change
T790M
Other names
-
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Links
PharmGKB Clinical Annotation: 981475450
UniProtKB: P00533#VAR_026098
OMIM: 131550.0006
dbSNP: rs121434569
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
drug response 1 reviewed by expert panel Jun 23, 2016 RCV000211140.1
drug response 1 reviewed by expert panel Jun 23, 2016 RCV000211319.1
Likely pathogenic 1 criteria provided, single submitter Jan 5, 2019 RCV000557450.4
protective 1 no assertion criteria provided Dec 24, 2009 RCV000018088.29
drug response 1 no assertion criteria provided Nov 11, 2014 RCV000154232.1
Pathogenic/Likely pathogenic 2 no assertion criteria provided Mar 10, 2016 RCV000154233.3
Likely pathogenic 1 no assertion criteria provided May 13, 2016 RCV000425417.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
EGFR - - GRCh38
GRCh37
245 318
EGFR-AS1 - - - GRCh38 - 61

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
drug response
Drug-variant association: Efficacy
(Jun 23, 2016)
reviewed by expert panel
Method: curation
gefitinib response - Efficacy
Drug used for Carcinoma, Non-Small-Cell Lung
Allele origin: germline
PharmGKB
Accession: SCV000268173.3
Submitted: (Jun 18, 2018)
Comment:
Drug is not necessarily used to treat response condition
Evidence details
Publications
PubMed (17)
Other databases
https://www.pharmgkb.org/clini...
Comment:
PharmGKB Level of Evidence 2A: Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) ... (more)
drug response
Drug-variant association: Efficacy
(Jun 23, 2016)
reviewed by expert panel
Method: curation
erlotinib response - Efficacy
Drug used for Carcinoma, Non-Small-Cell Lung
Allele origin: germline
PharmGKB
Accession: SCV000268172.3
Submitted: (Jun 18, 2018)
Comment:
Drug is not necessarily used to treat response condition
Evidence details
Publications
PubMed (17)
Other databases
https://www.pharmgkb.org/clini...
Comment:
PharmGKB Level of Evidence 2A: Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) ... (more)
Likely pathogenic
(Jan 05, 2019)
criteria provided, single submitter
Method: clinical testing
EGFR-related lung cancer
Allele origin: germline
Invitae
Accession: SCV000658980.4
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (12)
Comment:
This sequence change replaces threonine with methionine at codon 790 of the EGFR protein (p.Thr790Met). The threonine residue is highly conserved and there is a ... (more)
drug response
Resistant
(Nov 11, 2014)
no assertion criteria provided
Method: clinical testing
Tyrosine kinase inhibitor response
Allele origin: somatic
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine
Accession: SCV000203887.1
Submitted: (Jan 29, 2015)
Evidence details
Publications
PubMed (15)
Comment:
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 ... (more)
Likely pathogenic
(Nov 11, 2014)
no assertion criteria provided
Method: clinical testing
Non-Small Cell Lung Cancer
Allele origin: germline
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine
Accession: SCV000203888.1
Submitted: (Jan 29, 2015)
Evidence details
Publications
PubMed (15)
Comment:
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 ... (more)
protective
(Dec 24, 2009)
no assertion criteria provided
Method: literature only
NONSMALL CELL LUNG CANCER, RESISTANCE TO TYROSINE KINASE INHIBITOR IN
Allele origin: unknown
OMIM
Accession: SCV000038367.2
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (6)
Pathogenic
(Mar 10, 2016)
no assertion criteria provided
Method: literature only
Non-small cell lung cancer
(Somatic mutation)
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000504237.1
Submitted: (Jul 18, 2016)
Evidence details
Publications
PubMed (30)
Other databases
http://docm.genome.wustl.edu/v...
Likely pathogenic
(May 13, 2016)
no assertion criteria provided
Method: literature only
Lung cancer
(Somatic mutation)
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000504238.1
Submitted: (Jul 18, 2016)
Evidence details
Publications
PubMed (2)
Other databases
http://docm.genome.wustl.edu/v...

Citations for this variant

Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Osimertinib Responses After Disease Progression in Patients Who Had Been Receiving Rociletinib. Sequist LV JAMA oncology 2016 PMID: 26720284
Germline Mutation of T790M and Dual/Multiple EGFR Mutations in Patients With Lung Adenocarcinoma. Lou Y Clinical lung cancer 2016 PMID: 26700910
In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Hirano T Oncotarget 2015 PMID: 26515464
Rociletinib in EGFR-mutated non-small-cell lung cancer. Sequist LV The New England journal of medicine 2015 PMID: 25923550
AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. Jänne PA The New England journal of medicine 2015 PMID: 25923549
EGFR T790M resistance mutation in non small-cell lung carcinoma. Denis MG Clinica chimica acta; international journal of clinical chemistry 2015 PMID: 25668228
Prospective enterprise-level molecular genotyping of a cohort of cancer patients. MacConaill LE The Journal of molecular diagnostics : JMD 2014 PMID: 25157968
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cross DA Cancer discovery 2014 PMID: 24893891
Germline EGFR T790M mutation found in multiple members of a familial cohort. Yu HA Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2014 PMID: 24736080
Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. Gazdar A Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2014 PMID: 24736066
Primary concomitant EGFR T790M mutation predicted worse prognosis in non-small cell lung cancer patients. Li H OncoTargets and therapy 2014 PMID: 24729716
A systematic profile of clinical inhibitors responsive to EGFR somatic amino acid mutations in lung cancer: implication for the molecular mechanism of drug resistance and sensitivity. Ai X Amino acids 2014 PMID: 24658966
Response to pemetrexed rechallenge after acquired resistance of EGFR-TKI in a patient with advanced NSCLC. Li S Lung cancer (Amsterdam, Netherlands) 2014 PMID: 24636847
The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progression-free survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis. Ding D OncoTargets and therapy 2014 PMID: 24623981
Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Yu HA Annals of oncology : official journal of the European Society for Medical Oncology 2014 PMID: 24478319
A patient with metastatic lung adenocarcinoma harboring concurrent EGFR L858R, EGFR germline T790M, and PIK3CA mutations: the challenge of interpreting results of comprehensive mutational testing in lung cancer. Lammers PE Journal of the National Comprehensive Cancer Network : JNCCN 2014 PMID: 24453288
The quest to overcome resistance to EGFR-targeted therapies in cancer. Chong CR Nature medicine 2013 PMID: 24202392
Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Walter AO Cancer discovery 2013 PMID: 24065731
LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. Katakami N Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013 PMID: 23816963
Concurrent molecular alterations in tumors with germ line epidermal growth factor receptor T790M mutations. Thomas A Clinical lung cancer 2013 PMID: 23540867
MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib. Huang MH Molecular oncology 2013 PMID: 23102728
Screening for germline EGFR T790M mutations through lung cancer genotyping. Oxnard GR Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2012 PMID: 22588155
Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Miller VA The Lancet. Oncology 2012 PMID: 22452896
Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. Su KY Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012 PMID: 22215752
A noninvasive system for monitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors with plasma DNA. Nakamura T Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2011 PMID: 21921847
Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Wu JY Clinical cancer research : an official journal of the American Association for Cancer Research 2011 PMID: 21531810
Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sequist LV Science translational medicine 2011 PMID: 21430269
Inherited germline T790M mutation and somatic epidermal growth factor receptor mutations in non-small cell lung cancer patients. Tibaldi C Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2011 PMID: 21252721
Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Arcila ME Clinical cancer research : an official journal of the American Association for Cancer Research 2011 PMID: 21248300
Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Rosell R Clinical cancer research : an official journal of the American Association for Cancer Research 2011 PMID: 21233402
Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis. Watanabe S BMC cancer 2011 PMID: 21194487
Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Turke AB Cancer cell 2010 PMID: 20129249
Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Girard N Clinical cancer research : an official journal of the American Association for Cancer Research 2010 PMID: 20068085
Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status. Onitsuka T Lung cancer (Amsterdam, Netherlands) 2010 PMID: 19589612
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Zhou W Nature 2009 PMID: 20033049
Clinicopathologic and molecular features of epidermal growth factor receptor T790M mutation and c-MET amplification in tyrosine kinase inhibitor-resistant Chinese non-small cell lung cancer. Chen HJ Pathology oncology research : POR 2009 PMID: 19381876
Germ-line and somatic presentations of the EGFR T790M mutation in lung cancer. Prudkin L Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2009 PMID: 19096324
Prospective phase II study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations. Sugio K Lung cancer (Amsterdam, Netherlands) 2009 PMID: 18992959
Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Costa DB Clinical cancer research : an official journal of the American Association for Cancer Research 2008 PMID: 18981003
Detection of mutations in EGFR in circulating lung-cancer cells. Maheswaran S The New England journal of medicine 2008 PMID: 18596266
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Yun CH Proceedings of the National Academy of Sciences of the United States of America 2008 PMID: 18227510
MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Bean J Proceedings of the National Academy of Sciences of the United States of America 2007 PMID: 18093943
Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. Regales L PloS one 2007 PMID: 17726540
EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Vikis H Cancer research 2007 PMID: 17510392
Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib. Mulloy R Cancer research 2007 PMID: 17332364
Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Balak MN Clinical cancer research : an official journal of the American Association for Cancer Research 2006 PMID: 17085664
Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Kosaka T Clinical cancer research : an official journal of the American Association for Cancer Research 2006 PMID: 17020982
Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Inukai M Cancer research 2006 PMID: 16912157
Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Bell DW Nature genetics 2005 PMID: 16258541
EGFR mutation and response of lung cancer to gefitinib. Toyooka S The New England journal of medicine 2005 PMID: 15901872
Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. Pao W PLoS medicine 2005 PMID: 15737014
EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. Kobayashi S The New England journal of medicine 2005 PMID: 15728811
EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Pao W Proceedings of the National Academy of Sciences of the United States of America 2004 PMID: 15329413
A major lung cancer susceptibility locus maps to chromosome 6q23-25. Bailey-Wilson JE American journal of human genetics 2004 PMID: 15272417
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Paez JG Science (New York, N.Y.) 2004 PMID: 15118125
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. Lynch TJ The New England journal of medicine 2004 PMID: 15118073
Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Gorre ME Science (New York, N.Y.) 2001 PMID: 11423618
http://docm.genome.wustl.edu/variants/ENST00000275493:c.2369C>T - - - -
https://www.pharmgkb.org/clinicalAnnotation/981475450 - - - -

Record last updated Aug 16, 2019