rs397517109

Positions:

• chr7-55181309-C-CCAGCGTGGA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_005228.5(EGFR):​c.2303_2311dup​(p.Ser768_Asp770dup) variant causes a 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 (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: EGFR NM_005228.5 inframe_insertion
• Clinical Significance: drug response criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 2.52

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005228.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2303_2311dup	p.Ser768_Asp770dup	inframe_insertion	20/28	ENST00000275493.7	NP_005219.2
EGFR-AS1	NR_047551.1	n.1261_1262insTCCACGCTG		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2303_2311dup	p.Ser768_Asp770dup	inframe_insertion	20/28	1	NM_005228.5	ENSP00000275493	P1
EGFR-AS1	ENST00000442411.2	n.1289_1290insTCCACGCTG		non_coding_transcript_exon_variant	2/2	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

Likely pathogenic, no assertion criteria provided

clinical testing

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

-

- -

Non-small cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 28, 2006

- -

Tyrosine kinase inhibitor response Other:1

drug response, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 01, 2012

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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517109; hg19: chr7-55249002;