chr7-55174774-AATTAAGAGA-C

Variant names:

• chr7-55174774-AATTAAGAGA-C
• rs727504444
• NM_005228.5:c.2237_2246delAATTAAGAGAinsC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_005228.5(EGFR):​c.2237_2246delAATTAAGAGAinsC​(p.Glu746_Glu749delinsAla) variant causes a missense, conservative 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 drug response (★). Synonymous variant affecting the same amino acid position (i.e. E746null) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense, conservative_inframe_deletion
• Clinical Significance: drug response criteria provided, single submitter O:1
• Conservation: PhyloP100: 9.89
• Publications: 2 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 Gene-Disease associations (from GenCC):

• lung cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• non-small cell lung carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• inflammatory skin and bowel disease, neonatal, 2

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 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.2237_2246delAATTAAGAGAinsC	p.Glu746_Glu749delinsAla	missense_variant, conservative_inframe_deletion	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.2237_2246delAATTAAGAGAinsC	p.Glu746_Glu749delinsAla	missense_variant, conservative_inframe_deletion	Exon 19 of 28	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.2102_2111delAATTAAGAGAinsC	p.Glu701_Glu704delinsAla	missense_variant, conservative_inframe_deletion	Exon 18 of 26	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.2078_2087delAATTAAGAGAinsC	p.Glu693_Glu696delinsAla	missense_variant, conservative_inframe_deletion	Exon 19 of 28	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.584_593delAATTAAGAGAinsC	p.Glu195_Glu198delinsAla	missense_variant, conservative_inframe_deletion	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

Apr 04, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 2237_2246delinsC variant in exon 19 of EGFR has not been previously reported in the literature or identified by our laboratory. This variant results in an in-frame deletion and insertion and is located in the protein kinase domain of EGFR. In-frame deletions in the kinase domain of EGFR have been shown to correlate with responsiveness to tyrosine-kinase inhibitor (TKI, Paez 2004, Lynch 2004). Likely Responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

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

Other links and lift over

dbSNP: rs727504444; hg19: chr7-55242467;