rs121913421

Positions:

• chr7-55174771-AGGAATTAAGAGAAGC-A

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_2249del​(p.Glu746_Ala750del) variant causes a 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 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 modified_residue N6-(2-hydroxyisobutyryl)lysine (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/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2235_2249del	p.Glu746_Ala750del	inframe_deletion	19/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2235_2249del	p.Glu746_Ala750del	inframe_deletion	19/28	1	NM_005228.5	ENSP00000275493	P1
EGFR	ENST00000455089.5	c.2100_2114del	p.Glu701_Ala705del	inframe_deletion	18/26	1		ENSP00000415559
EGFR	ENST00000450046.2	c.2076_2090del	p.Glu693_Ala697del	inframe_deletion	19/28	4		ENSP00000413354
EGFR	ENST00000700145.1	c.584_598del	p.Glu196_Ala200del	inframe_deletion	6/9			ENSP00000514824

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

Likely pathogenic, no assertion criteria provided	clinical testing	Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University	-	- -
Pathogenic, criteria provided, single submitter	research	Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research	Jun 06, 2022	- -

EGFR-related lung cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2022

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). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 163343). This variant is not present in population databases (gnomAD no frequency). 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. -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Tyrosine kinase inhibitor response Other:1

drug response, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 28, 2006

- 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;