chr7-55155917-G-T

Variant names:

• chr7-55155917-G-T
• rs886037891
• NM_005228.5:c.977G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_005228.5(EGFR):​c.977G>T​(p.Cys326Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C326S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.97
• Publications: 10 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 7-55155917-G-T is Pathogenic according to our data. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-55155917-G-T is described in CliVar as Pathogenic. Clinvar id is 254143.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.977G>T	p.Cys326Phe	missense_variant	Exon 8 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.977G>T	p.Cys326Phe	missense_variant	Exon 8 of 28	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1

Aug 24, 2016

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- Mutation has not been reported in 1000G, NHLBI-ESP, and ExAC databases - Mutation occurs in a highly conserved amino acid residue - Predicted as damaging according to multiple computational algorithms (SIFT, PolyPhen-2, MutationTaster, MutPred, Condel, and Project HOPE) - Functional data supportive of a gain-of-function effect -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;D;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.9	.;H;.;H;H;H;.
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-10	D;D;.;D;D;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.
Polyphen		1.0	D;D;.;D;D;D;.
Vest4		0.92
MutPred		0.90		.;Gain of catalytic residue at C326 (P = 0.0191);.;Gain of catalytic residue at C326 (P = 0.0191);Gain of catalytic residue at C326 (P = 0.0191);Gain of catalytic residue at C326 (P = 0.0191);.;
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs886037891; hg19: chr7-55223610; COSMIC: COSV51855854;