rs121434569
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP3_StrongPP5_Strong
The NM_005228(EGFR):c.2369C>T(p.Thr790Met) variant causes a missense change. The variant allele was found at a frequency of 0.000046 in 152222 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Synonymous variant affecting the same amino acid position (i.e. T790T) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
EGFR
NM_005228 missense
NM_005228 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: 4.95
Links
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a domain Protein kinase (size 267) in uniprot entity EGFR_HUMAN there are 48 pathogenic changes around while only 7 benign (87%) in NM_005228
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=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EGFR | NM_005228.5 | c.2369C>T | p.Thr790Met | missense_variant | 20/28 | ENST00000275493.7 | |
EGFR-AS1 | NR_047551.1 | 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 | c.2369C>T | p.Thr790Met | missense_variant | 20/28 | 1 | NM_005228.5 | P1 | |
EGFR-AS1 | ENST00000442411.2 | n.1221G>A | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251464Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
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ClinVar
Significance: drug response
Submissions summary: Pathogenic:7Benign:1Other:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Non-small cell lung carcinoma Pathogenic:2
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. - |
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Mar 10, 2016 | - - |
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 |
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) - |
Lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
EGFR-related lung cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | 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. 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. - |
Lung cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine | - | 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. - |
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. - |
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 | 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 |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Pathogenic
DEOGEN2
Uncertain
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MutPred
0.91
.;.;Loss of catalytic residue at T790 (P = 0.0799);
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at