7-55174774-AATTAAGAGAAG-AGC

Variant names:

• chr7-55174775-ATTAAGAGAAG-GC
• rs121913435
• NM_005228.5:c.2238_2248delATTAAGAGAAGinsGC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_005228.5(EGFR):​c.2238_2248delATTAAGAGAAGinsGC​(p.Leu747_Ala750delinsPro) 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 (★). Synonymous variant affecting the same amino acid position (i.e. ELREAT746EP) has been classified as Uncertain significance.

• 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 Likely_pathogenic. Variant got 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 2 benign, 14 uncertain in NM_005228.5
• 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 rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2238_2248delATTAAGAGAAGinsGC	p.Leu747_Ala750delinsPro	disruptive_inframe_deletion, synonymous_variant	Exon 19 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2238_2248delATTAAGAGAAGinsGC	p.Leu747_Ala750delinsPro	disruptive_inframe_deletion, synonymous_variant	Exon 19 of 28	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.2103_2113delATTAAGAGAAGinsGC	p.Leu702_Ala705delinsPro	disruptive_inframe_deletion, synonymous_variant	Exon 18 of 26	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.2079_2089delATTAAGAGAAGinsGC	p.Leu694_Ala697delinsPro	disruptive_inframe_deletion, synonymous_variant	Exon 19 of 28	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.585_595delATTAAGAGAAGinsGC	p.Leu196_Ala199delinsPro	disruptive_inframe_deletion, synonymous_variant	Exon 6 of 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

Aug 09, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- 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: rs121913435; hg19: chr7-55242468; COSMIC: COSV51782279; COSMIC: COSV51782279;