7-55155917-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_005228.5(EGFR):​c.977G>T​(p.Cys326Phe) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

EGFR
NM_005228.5 missense

Scores

15
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.97
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 7-55155917-G-T is Pathogenic according to our data. Variant chr7-55155917-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EGFRNM_005228.5 linkc.977G>T p.Cys326Phe missense_variant Exon 8 of 28 ENST00000275493.7 NP_005219.2 P00533-1Q504U8F2YGG7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EGFRENST00000275493.7 linkc.977G>T p.Cys326Phe missense_variant Exon 8 of 28 1 NM_005228.5 ENSP00000275493.2 P00533-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1
Aug 24, 2016
Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- Mutation has not been reported in 1000G, NHLBI-ESP, and ExAC databases - Mutation occurs in a highly conserved amino acid residue - Predicted as damaging according to multiple computational algorithms (SIFT, PolyPhen-2, MutationTaster, MutPred, Condel, and Project HOPE) - Functional data supportive of a gain-of-function effect -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
D;.;D;.;.;D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
3.9
.;H;.;H;H;H;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-10
D;D;.;D;D;D;.
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;.;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;.
Polyphen
1.0
D;D;.;D;D;D;.
Vest4
0.92
MutPred
0.90
.;Gain of catalytic residue at C326 (P = 0.0191);.;Gain of catalytic residue at C326 (P = 0.0191);Gain of catalytic residue at C326 (P = 0.0191);Gain of catalytic residue at C326 (P = 0.0191);.;
MVP
0.98
MPC
1.8
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.99
gMVP
1.0

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: rs886037891; hg19: chr7-55223610; COSMIC: COSV51855854; API