rs483352806

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_005228.5(EGFR):c.2327G>A(p.Arg776His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R776C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

EGFR
NM_005228.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3O:1

Conservation

PhyloP100: 9.96

Variant links:

Genes affected

EGFR (HGNC:3236): (epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]

EGFR links:

EGFR-AS1 (HGNC:40207): (EGFR antisense RNA 1)

EGFR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005228.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 7-55181336-G-A is Pathogenic according to our data. Variant chr7-55181336-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126515.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.2327G>A	p.Arg776His	missense_variant	20/28	ENST00000275493.7
EGFR-AS1	NR_047551.1 linkuse as main transcript	n.1235C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.2327G>A	p.Arg776His	missense_variant	20/28	1	NM_005228.5	P1	P00533-1
EGFR-AS1	ENST00000442411.2 linkuse as main transcript	n.1263C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251306

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

EGFR-related lung cancer

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Thoracic Oncology Program, Dana-Farber Cancer Institute	Nov 17, 2022	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 21, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2023	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. -

Lung cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Dec 29, 2022

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]. -

Squamous cell carcinoma of the head and neck

Other:1

drug response, no assertion criteria provided

literature only

Genetics, Bhagwan Mahavir Medical Research Centre

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

-0.17

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.5

D;.;D

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.94

MutPred

0.78

.;.;Gain of catalytic residue at L778 (P = 0.0352);

MVP

0.96

MPC

1.6

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over