rs397517106

Positions:

• chr7-55181287-C-CTCCAGGAAGCCT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_005228.5(EGFR):​c.2284-5_2290dup variant causes a splice region, splice polypyrimidine tract, intron 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: EGFR NM_005228.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.27

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
• 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/exons	MANE	UniProt
EGFR	NM_005228.5	c.2284-5_2290dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000275493.7
EGFR-AS1	NR_047551.1	n.1283_1284insAGGCTTCCTGGA		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2284-5_2290dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005228.5	P1
EGFR-AS1	ENST00000442411.2	n.1311_1312insAGGCTTCCTGGA		non_coding_transcript_exon_variant	2/2	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2011

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517106; hg19: chr7-55248980;