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rs121434568

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_005228.5(EGFR):c.2573T>A(p.Leu858Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L858R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

EGFR
NM_005228.5 missense

Scores

15
2
1

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.96
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 3 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-55191822-T-G is described in ClinVar as [drug_response]. Clinvar id is 16609.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {drug_response=1, other=2, Pathogenic=2}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 7-55191822-T-A is Pathogenic according to our data. Variant chr7-55191822-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376281.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFRNM_005228.5 linkuse as main transcriptc.2573T>A p.Leu858Gln missense_variant 21/28 ENST00000275493.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFRENST00000275493.7 linkuse as main transcriptc.2573T>A p.Leu858Gln missense_variant 21/281 NM_005228.5 P1P00533-1
EGFRENST00000455089.5 linkuse as main transcriptc.2438T>A p.Leu813Gln missense_variant 20/261
EGFRENST00000450046.2 linkuse as main transcriptc.2414T>A p.Leu805Gln missense_variant 21/284
EGFRENST00000700145.1 linkuse as main transcriptc.899+23T>A intron_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
Cadd
Pathogenic
32
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;D;D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.2
D;.;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.99
MutPred
0.89
.;.;Gain of disorder (P = 0.0531);
MVP
0.99
MPC
1.5
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.95
gMVP
0.97

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.

Other links and lift over

dbSNP: rs121434568; hg19: chr7-55259515; COSMIC: COSV51854030; COSMIC: COSV51854030; API