rs397517086

Positions:

• chr7-55173985-AAAC-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_005228.5(EGFR):​c.2127_2129del​(p.Glu709_Thr710delinsAsp) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005228.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-55173985-AAAC-A is Pathogenic according to our data. Variant chr7-55173985-AAAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 45220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2127_2129del	p.Glu709_Thr710delinsAsp	inframe_deletion	18/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2127_2129del	p.Glu709_Thr710delinsAsp	inframe_deletion	18/28	1	NM_005228.5	ENSP00000275493	P1
EGFR	ENST00000455089.5	c.1992_1994del	p.Glu664_Thr665delinsAsp	inframe_deletion	17/26	1		ENSP00000415559
EGFR	ENST00000450046.2	c.1968_1970del	p.Glu656_Thr657delinsAsp	inframe_deletion	18/28	4		ENSP00000413354
EGFR	ENST00000700145.1	c.476_478del	p.Glu159_Thr160delinsAsp	inframe_deletion	5/9			ENSP00000514824

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 15, 2011

The Glu709_Thr710delinsAsp variant has been previously reported as a somatic variant in the literature in several individuals with lung adenocarcinoma (Reinmuth 2008, COSMIC). TKI response was not evaluated in these individuals. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs397517086; hg19: chr7-55241678; COSMIC: COSV51779132; COSMIC: COSV51779132;