Submissions for variant NM_005228.5(EGFR):c.2327G>A (p.Arg776His)

gnomAD frequency: 0.00001  dbSNP: rs483352806

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002444563	SCV000197937	uncertain significance	Hereditary cancer-predisposing syndrome	2017-04-21	criteria provided, single submitter	clinical testing	The p.Arg776His variant in EGFR has been reported in 10 lung carcinomas, at least 9 of which had another known driver EGFR variant (Arcila et al. 2013, Imielinski et al. 2012, Kobayashi et al. 2013, Lim et al. 2009, Lin et al. 2014, Peng et al. 2014, Sequist et al. 2007, van Noesel et al. 2013, Wu et al. 2008). In 1 of these individuals, the p.Arg776His variant was confirmed to be present in the germline, and it segregated with lung cancer in 1 affected relative (van Noesel et al. 2013). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg776His variant may impact protein function (van Noesel et al. 2013 and Ruan et al. 2015); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg776His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg776His variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229177	SCV001401615	uncertain significance	EGFR-related lung cancer	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 776 of the EGFR protein (p.Arg776His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with lung cancer (PMID: 23358982, 25969368, 34555730; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126515). 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: 23358982, 26101090, 28874603). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002444563	SCV002732464	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.R776H variant (also known as c.2327G>A), located in coding exon 20 of the EGFR gene, results from a G to A substitution at nucleotide position 2327. The arginine at codon 776 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in the germline of individuals with a personal and/or family history of lung cancer (van Noesel J et al. J. Clin. Oncol. 2013 Apr;31:e161-4; Belardinilli F et al. Int. J. Biol. Markers. 2018 Jun;:1724600818782200; Li D et al. Onco Targets Ther, 2023 Jan;16:17-22). Functional studies have shown that this alteration leads to constitutive EGFR activation and catalytic activity in the absence of ligand (van Noesel J et al. J. Clin. Oncol. 2013 Apr;31:e161-4; McSkimming DI et al. Hum. Mutat. 2015 Feb;36:175-86; Ruan Z et al. Biochemistry. 2015 Jul;54:4216-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Thoracic Oncology Program, Dana-Farber Cancer Institute	RCV001229177	SCV002757873	pathogenic	EGFR-related lung cancer	2022-11-17	criteria provided, single submitter	clinical testing	Here we report a family of germline EGFR R776H carriers with highly penetrant non-small cell lung cancer (NSCLC) and lung nodules in multiple generations. The EGFR R776H variant was confirmed to be present and segregated with lung cancer in all affected family members (n=4) and also with lung nodules in additional family members (n=4). The EGFR R776H germline mutation has also been reported in additional families with high incidence of multiple primary lung cancers (van Noesel et al, J Clin Oncol 2013;31:e161-4) and segregated with lung cancer in affected family members. This variant is present in public databases at frequency of 0.000003979 (gnomAD v2.1.1) and 0.000006570 (gnomAD v3.1.2), and not present in individuals of East Asian ancestry. The gain-of-function R776H variant has been reported as an activating oncogenic driver in EGFR-mutant lung cancer, often co-existing with additional somatic EGFR mutations EGFR L858R and EGFR G719A/S, and responsive to EGFR tyrosine kinase inhibitors (Gaili et al, Journal of Clinical Oncology 2021 39:15_suppl, e21001-e21001, https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.e21001). Additional studies detecting the EGFR R776H somatic variant in EGFR-related NSCLC exist (Guo T, Zhu L, Li W, Lin R, Ding Y, Kang Q, Shao L, Li C, Pan X. Two cases of non-small cell lung cancer patients with somatic or germline EGFR R776H mutation. Lung Cancer. 2021 Nov;161:94-97, He SY, Lin QF, Chen J, Yu GP, Zhang JL, Shen D. Efficacy of afatinib in a patient with rare EGFR (G724S/R776H) mutations and amplification in lung adenocarcinoma: A case report. World J Clin Cases. 2021 Feb 26;9(6):1329-1335). In vitro studies have found the R776H EGFR mutation in the αC-β4 loop of the tyrosine kinase domain to activate EGFR in the absence of the activating EGF ligand, supporting evidence for a gain-of-function variant (Ruan Z, Kannan N. Mechanistic Insights into R776H Mediated Activation of Epidermal Growth Factor Receptor Kinase. Biochemistry. 2015 Jul 14;54(27):4216-25, Ruan Z, Kannan N. Altered conformational landscape and dimerization dependency underpins the activation of EGFR by αC-β4 loop insertion mutations. Proc Natl Acad Sci U S A. 2018 Aug 28;115(35):E8162-E8171, and van Noesel et al 2013). In summary, the EGFR Arg776His variant meets our criteria to be classified as pathogenic (https://personalizedmedicine.partners.org/Assets/documents/Laboratory-For-Molecular-Medicine/LMM_Variant_Assessment_Principles_10.8.14.pdf) based upon segregation studies, relative absence from controls, and functional evidence. Using criteria from PMID 25741868, this variant meets criteria for Pathogenic (PS3 and PM1, PM2, and PP1, PP2, PP4).
Myriad Genetics, Inc.	RCV003137628	SCV003806592	likely pathogenic	Lung cancer	2022-12-29	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23358982, 25382819, 26101090]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23358982, 34555730, 29945477, 29576263, 33898318].
Genetics, Bhagwan Mahavir Medical Research Centre	RCV000114404	SCV000148121	drug-response	Squamous cell carcinoma of the head and neck		no assertion criteria provided	not provided	Converted during submission to drug response.