chr7-55181318-A-AGTC

Position:

• chr7-55181318-A-AGTC

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.2309_2310insGTC​(p.Asp770delinsGluSer) variant causes a disruptive inframe insertion 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: EGFR NM_005228.5 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.44

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:):

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 7-55181318-A-AGTC is Pathogenic according to our data. Variant chr7-55181318-A-AGTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496810.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.2309_2310insGTC	p.Asp770delinsGluSer	disruptive_inframe_insertion	20/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2309_2310insGTC	p.Asp770delinsGluSer	disruptive_inframe_insertion	20/28	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics, Rajiv Gandhi Cancer Institute & Research Center

Dec 12, 2017

In-frame insertion of 'GTC' in exon 20 of EGFR is a negative predictor of drug response to anti EGFR TKIs. This inference is being drawn based upon similar insertions in this region of exon 20. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554350382; hg19: chr7-55249011;