rs727504257

Positions:

• chr7-55174774-AATTAAGAGAAGCAA-AGC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_005228.5(EGFR):​c.2238_2251delATTAAGAGAAGCAAinsGC​(p.Leu747_Thr751delinsPro) variant causes a disruptive inframe deletion, synonymous 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 drug response (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 disruptive_inframe_deletion, synonymous
• Clinical Significance: drug response criteria provided, single submitter O:1
• Conservation: PhyloP100: 9.89

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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2238_2251delATTAAGAGAAGCAAinsGC	p.Leu747_Thr751delinsPro	disruptive_inframe_deletion, synonymous_variant	19/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2238_2251delATTAAGAGAAGCAAinsGC	p.Leu747_Thr751delinsPro	disruptive_inframe_deletion, synonymous_variant	19/28	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.2103_2116delATTAAGAGAAGCAAinsGC	p.Leu702_Thr706delinsPro	disruptive_inframe_deletion, synonymous_variant	18/26	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.2079_2092delATTAAGAGAAGCAAinsGC	p.Leu694_Thr698delinsPro	disruptive_inframe_deletion, synonymous_variant	19/28	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.585_598delATTAAGAGAAGCAAinsGC	p.Leu196_Thr200delinsPro	disruptive_inframe_deletion, synonymous_variant	6/9			ENSP00000514824.1

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: drug response

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tyrosine kinase inhibitor response Other:1

drug response, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 23, 2012

- Responsive

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: rs727504257; hg19: chr7-55242468; COSMIC: COSV51803491; COSMIC: COSV51803491;