rs397517109

Variant names:

• chr7-55181309-C-CCAGCGTGGA
• rs397517109
• NM_005228.5:c.2303_2311dupGCGTGGACA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_005228.5(EGFR):​c.2303_2311dupGCGTGGACA​(p.Ser768_Asp770dup) variant causes a disruptive inframe insertion change involving the alteration of a non-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. N771N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: EGFR NM_005228.5 disruptive_inframe_insertion
• Clinical Significance: drug response criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 2.52
• Publications: 17 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-AS1 (HGNC:40207): (EGFR antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 25 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.

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.2303_2311dupGCGTGGACA	p.Ser768_Asp770dup	disruptive_inframe_insertion	Exon 20 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.2168_2176dupGCGTGGACA	p.Ser723_Asp725dup	disruptive_inframe_insertion	Exon 19 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.2144_2152dupGCGTGGACA	p.Ser715_Asp717dup	disruptive_inframe_insertion	Exon 20 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.2303_2311dupGCGTGGACA	p.Ser768_Asp770dup	disruptive_inframe_insertion	Exon 20 of 28	ENSP00000275493.2
	EGFR	ENST00000455089.5	TSL:1	c.2168_2176dupGCGTGGACA	p.Ser723_Asp725dup	disruptive_inframe_insertion	Exon 19 of 26	ENSP00000415559.1
	EGFR	ENST00000450046.2	TSL:4	c.2144_2152dupGCGTGGACA	p.Ser715_Asp717dup	disruptive_inframe_insertion	Exon 20 of 28	ENSP00000413354.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: drug response

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

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

Non-small cell lung carcinoma Pathogenic:1

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Tyrosine kinase inhibitor response Other:1

Jun 01, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser768_Asp770dup has been reported in the literature in at least four individuals that have been treated with an EGFR tyrosine kinase inhibitor (gefitinib; Wu 2008). Three of these individuals exhibited progressive disease and one individual exhibited partial response as the maximal response. Insertions in exon 20 of EGFR such as this have been associated with resistance to EGFR tyrosine kinase inhibitors in vitro (Greulich 2005). Likely Resistant

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

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

Other links and lift over

dbSNP: rs397517109; hg19: chr7-55249002; COSMIC: COSV51774688;