ClinVar Miner

Submissions for variant NM_005228.5(EGFR):c.2369C>T (p.Thr790Met) (rs121434569)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000211319 SCV000268172 drug response erlotinib response - Efficacy 2016-06-23 reviewed by expert panel curation 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) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.
PharmGKB RCV000211140 SCV000268173 drug response gefitinib response - Efficacy 2016-06-23 reviewed by expert panel curation 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) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.
Invitae RCV000557450 SCV000658980 likely pathogenic EGFR-related lung cancer 2020-01-06 criteria provided, single submitter clinical testing 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 moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121434569, ExAC 0.01%). This variant has been reported in individuals and families affected with lung cancer and pulmonary disease, many of whom were never smokers, and has been reported to segregate with disease (PMID: 16258541, 21252721, 24736066, 24736080, 23540867, 26700910). 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 (PMID: 24736066). However, these data should be further validated in studies with larger sample sizes. ClinVar contains an entry for this variant (Variation ID: 16613). The amino acid residue affected by this variant is located in the kinase domain of the EGFR protein and is critical for binding of EGFR kinase inhibitors, based on structural modeling (PMID: 15728811). Transgenic mice with inducible expression of this variant develop lung adenocarcinomas, and this variant is required for tumor maintenance (PMID: 17726540). In addition, experimental studies have shown that this variant enhances cell growth and confers drug resistance in vitro and in vivo (PMID: 15737014, 15728811, 17726540, 17510392, 18227510). Although this variant has been well characterized in cancer cells, functional studies demonstrating how this variant contributes to disease in the germline have not been reported. 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.
Ambry Genetics RCV001015308 SCV001176128 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses)
OMIM RCV000018088 SCV000038367 protective Nonsmall cell lung cancer, resistance to tyrosine kinase inhibitor in 2009-12-24 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154232 SCV000203887 drug response Tyrosine kinase inhibitor response 2014-11-11 no assertion criteria provided clinical testing 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).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154233 SCV000203888 likely pathogenic Non-small cell lung cancer 2014-11-11 no assertion criteria provided clinical testing 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.
Database of Curated Mutations (DoCM) RCV000154233 SCV000504237 pathogenic Non-small cell lung cancer 2016-03-10 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425417 SCV000504238 likely pathogenic Lung cancer 2016-05-13 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.