rs397517086

Variant names:

• chr7-55173985-AAAC-A
• rs397517086
• NM_005228.5:c.2127_2129delAAC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_005228.5(EGFR):​c.2127_2129delAAC​(p.Glu709_Thr710delinsAsp) variant causes a disruptive 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E709E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83
• Publications: 7 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: Uncertain_significance. The variant received 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 7-55173985-AAAC-A is Pathogenic according to our data. Variant chr7-55173985-AAAC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 45220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2127_2129delAAC	p.Glu709_Thr710delinsAsp	disruptive_inframe_deletion	Exon 18 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2127_2129delAAC	p.Glu709_Thr710delinsAsp	disruptive_inframe_deletion	Exon 18 of 28	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.1992_1994delAAC	p.Glu664_Thr665delinsAsp	disruptive_inframe_deletion	Exon 17 of 26	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.1968_1970delAAC	p.Glu656_Thr657delinsAsp	disruptive_inframe_deletion	Exon 18 of 28	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.474_476delAAC	p.Glu158_Thr159delinsAsp	disruptive_inframe_deletion	Exon 5 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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:1

Jun 15, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu709_Thr710delinsAsp variant has been previously reported as a somatic variant in the literature in several individuals with lung adenocarcinoma (Reinmuth 2008, COSMIC). TKI response was not evaluated in these individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397517086; hg19: chr7-55241678; COSMIC: COSV51779132; COSMIC: COSV51779132;