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GeneBe

rs121434568

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5

The NM_005228(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 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 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 missense

Scores

15
2
1

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.96

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
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: {Pathogenic=2, drug_response=3}.
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

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

Find out SpliceAI 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;