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

gnomAD frequency: 0.00005  dbSNP: rs121434569

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV000211319	SCV000268172	drug response	erlotinib response - Efficacy	2021-03-24	reviewed by expert panel	curation	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.
PharmGKB	RCV001787805	SCV002031219	drug response	gefitinib response - Efficacy	2021-03-24	reviewed by expert panel	curation	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557450	SCV000658980	likely pathogenic	EGFR-related lung cancer	2025-01-23	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV001015308	SCV001176128	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-08-02	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001588815	SCV001825948	likely pathogenic	not provided	2020-09-08	criteria provided, single submitter	clinical testing	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)
Neuberg Centre For Genomic Medicine, NCGM	RCV001823098	SCV002073070	pathogenic	Lung cancer		criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003466864	SCV004194584	pathogenic	Inflammatory skin and bowel disease, neonatal, 2	2023-12-07	criteria provided, single submitter	clinical testing
OMIM	RCV001823098	SCV000038367	pathogenic	Lung cancer	2009-12-24	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham 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, Mass General Brigham Personalized Medicine	RCV000154233	SCV000203888	likely pathogenic	Non-small cell lung carcinoma	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.
Institute of Medical Sciences, Banaras Hindu University	RCV000154232	SCV001571408	drug response	Tyrosine kinase inhibitor response	2020-10-30	no assertion criteria provided	research
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University	RCV003996105	SCV004042717	likely pathogenic	Lung adenocarcinoma		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752710	SCV005362384	likely pathogenic	EGFR-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The EGFR c.2369C>T variant is predicted to result in the amino acid substitution p.Thr790Met. This variant has been identified in multiple individuals with personal and/or family history of lung cancer, many of whom were never smokers (see for example, Bell et al. 2005. PubMed ID: 16258541; Gazdar et al 2014. PubMed ID: 24736066). In addition, this variant has been consistently demonstrated to affect tyrosine kinase inhibition in individuals with non-small cell lung cancers (see for example, Figure 1, Bell et al. 2005. PubMed ID: 16258541; Table 4, Chen et al. 2009. PubMed ID: 19381876; Table 1, Sequist et al. 2011. PubMed ID: 21430269). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. This variant has been classified as a drug response variant by an expert panel and is consistently classified as pathogenic and likely pathogenic by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/16613/). This variant is interpreted as likely pathogenic.