chr7-55154060-C-T

Variant names:

• chr7-55154060-C-T
• rs17336639
• NM_005228.5:c.797C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005228.5(EGFR):​c.797C>T​(p.Pro266Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P266S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59
• Publications: 0 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 Gene-Disease associations (from GenCC):

• lung cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• non-small cell lung carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• inflammatory skin and bowel disease, neonatal, 2

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	NM_005228.5	MANE Select	c.797C>T	p.Pro266Leu	missense	Exon 7 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.662C>T	p.Pro221Leu	missense	Exon 6 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.638C>T	p.Pro213Leu	missense	Exon 7 of 28	NP_001333829.1	C9JYS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.797C>T	p.Pro266Leu	missense	Exon 7 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000455089.5	TSL:1	c.662C>T	p.Pro221Leu	missense	Exon 6 of 26	ENSP00000415559.1	Q504U8
	EGFR	ENST00000344576.7	TSL:1	c.797C>T	p.Pro266Leu	missense	Exon 7 of 16	ENSP00000345973.2	P00533-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	EGFR-related lung cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	0.090
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.42
Sift	Benign	0.39	T
Sift4G	Benign	0.15	T
Polyphen		0.015	B
Vest4		0.65
MutPred		0.54		Gain of stability (P = 0.0311)
MVP		0.88
MPC		1.0
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.73
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17336639; hg19: chr7-55221753;