rs727503013

chr7-55181319-C-CAACCCCCCG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_005228.5(EGFR):c.2317_2318insCGAACCCCC(p.Pro772_His773insProAsnPro) variant causes a inframe insertion change. 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. D770D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: EGFR NM_005228.5 inframe_insertion
• Clinical Significance: drug response criteria provided, single submitter O:1
• Conservation: PhyloP100: 4.63

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.2317_2318insCGAACCCCC	p.Pro772_His773insProAsnPro	inframe_insertion	20/28	ENST00000275493.7
EGFR-AS1	NR_047551.1	n.1251_1252insCGGGGGGTT		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2317_2318insCGAACCCCC	p.Pro772_His773insProAsnPro	inframe_insertion	20/28	1	NM_005228.5	P1
EGFR-AS1	ENST00000442411.2	n.1279_1280insCGGGGGGTT		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: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tyrosine kinase inhibitor response Other:1

drug response, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 24, 2011

This variant has not been previously reported in the literature although similar insertions at this position have been described in cases of lung adenocarcinoma(Pro772_His773insTyrAsnPro, Pro772_His773insAspAsnPro, COSMIC, Wu 2008, Kosaka 2009). Insertions in EGFR exon 20 such as this have been associated with resistance to EGFR TKIs. 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: rs727503013; hg19: chr7-55249012;