rs397517106

Variant names:

• chr7-55181287-C-CTCCAGGAAGCCT
• rs397517106
• NM_005228.5:c.2284-5_2290dupTCCAGGAAGCCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP5_Moderate

The NM_005228.5(EGFR):​c.2284-5_2290dupTCCAGGAAGCCT​(p.Ala763_Tyr764insPheGlnGluAla) 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 (★). Synonymous variant affecting the same amino acid position (i.e. Y764Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: EGFR NM_005228.5 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.27
• 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-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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_005228.5
• PM4: Nonframeshift variant in NON repetitive region in NM_005228.5.
• PP5: Variant 7-55181287-C-CTCCAGGAAGCCT is Pathogenic according to our data. Variant chr7-55181287-C-CTCCAGGAAGCCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45248.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.2284-5_2290dupTCCAGGAAGCCT	p.Ala763_Tyr764insPheGlnGluAla	disruptive_inframe_insertion	Exon 20 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2284-5_2290dupTCCAGGAAGCCT	p.Ala763_Tyr764insPheGlnGluAla	disruptive_inframe_insertion	Exon 20 of 28	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:1

Jul 01, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a duplication at the 5' intron/exon boundary of exon 20 which results in the insertion of four amino acids. This variant has previously been reported in the literature in one lung carcinoma (Chen 2008, COSMIC). Insertions in EGFR exon 20 such as this have been associated with resistance to EGFR tyrosine kinase inhibitors; however, the likelihood of responsiveness of this individual cannot be determined conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs397517106; hg19: chr7-55248980;