7-55191746-T-G

Variant names:

• chr7-55191746-T-G
• rs397517126
• NM_005228.5:c.2497T>G
• EGFR p.Leu833Val

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_005228.5(EGFR):​c.2497T>G​(p.Leu833Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L833F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1 O:1
• Conservation: PhyloP100: 0.0230
• Publications: 146 publications found

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-AS1 (HGNC:40207): (EGFR antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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, 21 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 chr7-55191748-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2583129.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 7-55191746-T-G is Pathogenic according to our data. Variant chr7-55191746-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45277.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	NM_005228.5	MANE Select	c.2497T>G	p.Leu833Val	missense	Exon 21 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.2362T>G	p.Leu788Val	missense	Exon 20 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.2338T>G	p.Leu780Val	missense	Exon 21 of 28	NP_001333829.1	C9JYS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.2497T>G	p.Leu833Val	missense	Exon 21 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000455089.5	TSL:1	c.2362T>G	p.Leu788Val	missense	Exon 20 of 26	ENSP00000415559.1	Q504U8
	EGFR	ENST00000898199.1		c.2488T>G	p.Leu830Val	missense	Exon 21 of 28	ENSP00000568258.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lung adenocarcinoma (1)
-	1	-	not specified (1)
-	-	-	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.28	N
PhyloP100		0.023
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.37
Sift	Benign	0.035	D
Sift4G	Benign	0.10	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.65
Mutation Taster		=63/37	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397517126;

hg19: chr7-55259439;

COSMIC: COSV51773059;

COSMIC: COSV51773059;