chr7-55174775-ATTAAGAGAAGCAACATCT-A

Variant names:

• chr7-55174775-ATTAAGAGAAGCAACATCT-A
• rs121913440
• NM_005228.5:c.2239_2256delTTAAGAGAAGCAACATCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP3 PP5

The NM_005228.5(EGFR):​c.2239_2256delTTAAGAGAAGCAACATCT​(p.Leu747_Ser752del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic,drug response (no stars). Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic; drug response no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.89
• Publications: 34 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 6 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, 35 uncertain in NM_005228.5
• 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
• PP5: Variant 7-55174775-ATTAAGAGAAGCAACATCT-A is Pathogenic according to our data. Variant chr7-55174775-ATTAAGAGAAGCAACATCT-A is described in ClinVar as Likely_pathogenic|drug_response. ClinVar VariationId is 177647.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	NM_005228.5	MANE Select	c.2239_2256delTTAAGAGAAGCAACATCT	p.Leu747_Ser752del	conservative_inframe_deletion	Exon 19 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.2104_2121delTTAAGAGAAGCAACATCT	p.Leu702_Ser707del	conservative_inframe_deletion	Exon 18 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.2080_2097delTTAAGAGAAGCAACATCT	p.Leu694_Ser699del	conservative_inframe_deletion	Exon 19 of 28	NP_001333829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.2239_2256delTTAAGAGAAGCAACATCT	p.Leu747_Ser752del	conservative_inframe_deletion	Exon 19 of 28	ENSP00000275493.2
	EGFR	ENST00000455089.5	TSL:1	c.2104_2121delTTAAGAGAAGCAACATCT	p.Leu702_Ser707del	conservative_inframe_deletion	Exon 18 of 26	ENSP00000415559.1
	EGFR	ENST00000450046.2	TSL:4	c.2080_2097delTTAAGAGAAGCAACATCT	p.Leu694_Ser699del	conservative_inframe_deletion	Exon 19 of 28	ENSP00000413354.2

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: Likely pathogenic; drug response

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Lung adenocarcinoma Pathogenic:1

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Tyrosine kinase inhibitor response Other:1

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: clinical testing

Responsive

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=10/190	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs121913440; hg19: chr7-55242468; COSMIC: COSV51767308; COSMIC: COSV51767308;