rs28929495

chr7-55174014-G-Achr7-55174014-G-Cchr7-55174014-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2_SupportingPM5PP3_Strong

The NM_005228(EGFR):c.2155G>A(p.Gly719Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G719C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

EGFR
NM_005228 missense

Scores

Clinical Significance

Uncertain significance; drug response criteria provided, multiple submitters, no conflicts P:1U:1O:3

Conservation

PhyloP100: 9.90

Links

EGFR (HGNC:3236):

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a strand (size 9) in uniprot entity EGFR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005228

PM2

Very rare variant; Number of alleles below threshold, Median coverage is 33.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-55174015-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 45225. Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.2155G>A	p.Gly719Ser	missense_variant	18/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.2155G>A	p.Gly719Ser	missense_variant	18/28	1	NM_005228.5	P1	P00533-1
EGFR	ENST00000455089.5 linkuse as main transcript	c.2020G>A	p.Gly674Ser	missense_variant	17/26	1
EGFR	ENST00000450046.2 linkuse as main transcript	c.1996G>A	p.Gly666Ser	missense_variant	18/28	4
EGFR	ENST00000700145.1 linkuse as main transcript	c.505G>A	p.Gly169Ser	missense_variant	5/9

Frequencies

GnomAD3 genomes

Cov.:

ClinVar

Significance: Uncertain significance; drug response

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Non-small cell lung carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

EGFR-related lung cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2021

This sequence change replaces glycine with serine at codon 719 of the EGFR protein (p.Gly719Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant is a common somatic change in non-small cell lung cancer (NSCLC) (PMID: 29100434, 25061320, 23468066, 24039832). While this variant has been reported in the literature, it has not been reported in the germline of individuals with EGFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 16612). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in, somatic

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Jun 04, 2004

- -

Tyrosine kinase inhibitor response

Other:1

drug response, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 20, 2012

- Responsive

Neoplasm of the large intestine

Other:1

not provided, no assertion provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.77

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.1

D;.;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.94

MutPred

0.95

.;.;Gain of phosphorylation at G719 (P = 0.1215);

MVP

0.94

MPC

1.4

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.84

Splicing

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

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over