rs121913421

Variant names:

• chr7-55174771-AGGAATTAAGAGAAGC-A
• rs121913421
• NM_005228.5:c.2235_2249delGGAATTAAGAGAAGC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_005228.5(EGFR):​c.2235_2249delGGAATTAAGAGAAGC​(p.Glu746_Ala750del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:2
• Conservation: PhyloP100: 9.89

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a mutagenesis_site Abolishes kinase activity. (size 0) in uniprot entity EGFR_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005228.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-55174771-AGGAATTAAGAGAAGC-A is Pathogenic according to our data. Variant chr7-55174771-AGGAATTAAGAGAAGC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163343.We mark this variant Likely_pathogenic, oryginal submissions are: {other=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2235_2249delGGAATTAAGAGAAGC	p.Glu746_Ala750del	disruptive_inframe_deletion	Exon 19 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2235_2249delGGAATTAAGAGAAGC	p.Glu746_Ala750del	disruptive_inframe_deletion	Exon 19 of 28	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.2100_2114delGGAATTAAGAGAAGC	p.Glu701_Ala705del	disruptive_inframe_deletion	Exon 18 of 26	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.2076_2090delGGAATTAAGAGAAGC	p.Glu693_Ala697del	disruptive_inframe_deletion	Exon 19 of 28	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.582_596delGGAATTAAGAGAAGC	p.Glu195_Ala199del	disruptive_inframe_deletion	Exon 6 of 9			ENSP00000514824.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lung adenocarcinoma Pathogenic:2

Jun 06, 2022

Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

EGFR-related lung cancer Uncertain:1

Aug 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 163343). This variant, c.2235_2249del, results in the deletion of 5 amino acid(s) of the EGFR protein (p.Glu746_Ala750del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). While this variant has not been reported in the germline of individuals with EGFR-related disease, it is a commonly reported somatic change in lung cancer (PMID: 26066407, 29228562). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tyrosine kinase inhibitor response Other:1

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: clinical testing

- Responsive

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: rs121913421; hg19: chr7-55242464; COSMIC: COSV51765119; COSMIC: COSV51765119;