7-55191792-C-T

Variant names:

• chr7-55191792-C-T
• rs148934350
• NM_005228.5:c.2543C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP6 BS1

The NM_005228.5(EGFR):​c.2543C>T​(p.Pro848Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P848S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5 O:1
• Conservation: PhyloP100: 7.85
• Publications: 81 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-AS1 (HGNC:40207): (EGFR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005228.5
• BP6: Variant 7-55191792-C-T is Benign according to our data. Variant chr7-55191792-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45282.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000256 (39/152068) while in subpopulation NFE AF = 0.000485 (33/68034). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	NM_005228.5	MANE Select	c.2543C>T	p.Pro848Leu	missense	Exon 21 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.2408C>T	p.Pro803Leu	missense	Exon 20 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.2384C>T	p.Pro795Leu	missense	Exon 21 of 28	NP_001333829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.2543C>T	p.Pro848Leu	missense	Exon 21 of 28	ENSP00000275493.2
	EGFR	ENST00000455089.5	TSL:1	c.2408C>T	p.Pro803Leu	missense	Exon 20 of 26	ENSP00000415559.1
	EGFR	ENST00000450046.2	TSL:4	c.2384C>T	p.Pro795Leu	missense	Exon 21 of 28	ENSP00000413354.2

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251310 AF XY: 0.000383

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000385 AC: 563 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.000402 AC XY: 292 AN XY: 727228

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

American (AMR) AF: 0.000134 AC: 6 AN: 44724

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53386

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

European-Non Finnish (NFE) AF: 0.000466 AC: 518 AN: 1112008

Other (OTH) AF: 0.000331 AC: 20 AN: 60394

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74266

African (AFR) AF: 0.0000483 AC: 2 AN: 41406

American (AMR) AF: 0.000197 AC: 3 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 14, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the germline of individuals with lung cancer, glioma, and retinoblastoma (Sequist 2006, Prim 2014, Akhavanfard 2021); Published functional studies demonstrate reduced/absent auto-phosphorylation, kinase activity, and capacity to bind c-Cbl (de Gunst 2007, Sarcar 2019); This variant is associated with the following publications: (PMID: 22848293, 17877814, 25176975, 16857818, 33326033, 31314158)

May 01, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Jun 08, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the EGFR gene demonstrated a sequence change, c.2543C>T, in exon 21 that results in an amino acid change, p.Pro848Leu. This sequence change has been previously described in individuals with non-small cell lung cancer (NSCLC) (PMID: 25176975,16857818,22848293). In vitro functional studies have suggested that this variant is not a kinase activating mutation and showed a response to tyrosine kinase inhibitors, similar to the wild-type (PMID: 17877814, 22848293). This sequence change has been described in the gnomAD database with a frequency of 0.06% in the European subpopulation (dbSNP rs148934350). The p.Pro848Leu change affects a highly conserved amino acid residue located in a domain of the EGFR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro848Leu substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro848Leu change remains unknown at this time.

Jul 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro848Leu variant in Exon 21 of EGFR: This variant is not expected to have clinical significance because iIn vitro studies suggest that this variant does not activate EGFR activity and does not render the protein sensitive to tyrosine kinase inhibitors (TKIs) (De Gunst 2007, Han 2011). It has been previously identified in both tumor and normal tissue in an individuals with lung cancer (Sequist 2007), and it has been identified in 0.06% (6/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs148934350).

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Aug 23, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Nov 01, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Lung carcinoma Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EGFR-related lung cancer Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lung cancer Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 11-11-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.37	N
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.84
MPC		1.5
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.95
gMVP		0.82
Mutation Taster		=28/72	disease causing

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: rs148934350; hg19: chr7-55259485; COSMIC: COSV51773049;