rs1051753269

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005228.5(EGFR):c.2170G>A(p.Gly724Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EGFR
NM_005228.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.90

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.2170G>A	p.Gly724Ser	missense_variant	18/28	ENST00000275493.7	NP_005219.2	P00533-1Q504U8F2YGG7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.2170G>A	p.Gly724Ser	missense_variant	18/28	1	NM_005228.5	ENSP00000275493.2	P00533-1
EGFR	ENST00000455089.5 linkuse as main transcript	c.2035G>A	p.Gly679Ser	missense_variant	17/26	1		ENSP00000415559.1	Q504U8
EGFR	ENST00000450046.2 linkuse as main transcript	c.2011G>A	p.Gly671Ser	missense_variant	18/28	4		ENSP00000413354.2	C9JYS6
EGFR	ENST00000700145.1 linkuse as main transcript	c.517G>A	p.Gly173Ser	missense_variant	5/9			ENSP00000514824.1	A0A8V8TPW8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 25, 2019

The p.Gly724Ser variant has not been reported as a germline variant to our knowledge. However, this variant has been identified in 13 lung adenocarcinomas or non-small cell lung cancers (Brown 2019, Chung 2009, Fassunke 2018, Ogino 2005, Oztan 2017, Peled 2017, Tam 2006, Zhang 2019). In 11 of these cases, the p.Gly724Ser variant was only identified after progressive disease and in the setting of osimertinib and/or erlotinib resistance, often in the context of primary EGFR exon 19 deletions and acquired p.Thr790Met resistant mutation. Molecular modeling suggests that the p.Gly724Ser variant reduces osimertinib binding affinity in context of exon 19 deletion (Brown 2019), and in vitro functional evidence also supported that the p.Gly724Ser variant is resistant to osimertinib but may be responsive to afatinib (Brown 2019, Cho 2014, Fassunke 2018). This was also observed in one patient, where afatinib reduced the p.Gly724Ser clone identified in a metastatic liver lesion (Peled 2017). This variant has also been reported in two cases of colorectal cancer, one of which that did not respond to gefitinib (Cho 2014, Ogino 2005). In summary, while the clinical significance of this variant is uncertain in the context of a germline variant, there is evidence to support that the variant is likely resistant to osimertinib, a third-generation EGFR inhibitor in the setting of EGFR exon 19 deletions with or without in the acquired p.Thr790Met resistant mutation. -

EGFR-related lung cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 724 of the EGFR protein (p.Gly724Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with lung cancer (PMID: 30610926). ClinVar contains an entry for this variant (Variation ID: 376360). 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%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.2

.;.;M

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.91

MutPred

0.95

.;.;Gain of MoRF binding (P = 0.0868);

MVP

0.94

MPC

1.4

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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