chr7-55161509-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005228.5(EGFR):c.1509C>T(p.Gly503Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,058 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 12 hom., cov: 34)

Exomes 𝑓: 0.012 ( 102 hom. )

Consequence

EGFR
NM_005228.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.215

Publications

10 publications found

Variant links:

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

EGFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 7-55161509-C-T is Benign according to our data. Variant chr7-55161509-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.215 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00839 (1278/152382) while in subpopulation NFE AF = 0.0129 (879/68044). AF 95% confidence interval is 0.0122. There are 12 homozygotes in GnomAd4. There are 600 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5 link	c.1509C>T	p.Gly503Gly	synonymous_variant	Exon 13 of 28	ENST00000275493.7	NP_005219.2	P00533-1Q504U8F2YGG7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7 link	c.1509C>T	p.Gly503Gly	synonymous_variant	Exon 13 of 28	1	NM_005228.5	ENSP00000275493.2		P00533-1

Frequencies

GnomAD3 genomes

AF:

0.00839

AC:

1278

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00765

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0129

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00758

AC:

1902

AN:

250984

AF XY:

0.00783

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0140

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0116

AC:

17009

AN:

1461676

Hom.:

102

Cov.:

AF XY:

0.0114

AC XY:

8300

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33480

American (AMR)

AF:

0.00476

AC:

213

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00195

AC:

168

AN:

86242

European-Finnish (FIN)

AF:

0.0141

AC:

750

AN:

53252

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0136

AC:

15142

AN:

1111986

Other (OTH)

AF:

0.0103

AC:

620

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1024

2048

3072

4096

5120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

586

1172

1758

2344

2930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00839

AC:

1278

AN:

152382

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

600

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

41592

American (AMR)

AF:

0.00764

AC:

117

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0136

AC:

145

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0129

AC:

879

AN:

68044

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00749

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00998

EpiControl

AF:

0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EGFR: BP4, BP7, BS1, BS2 -

not specified

Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EGFR p.Gly503Gly variant was identified in the literature in a Korean cohort of 27 lung cancer cases (frequency: 0.41) and 27 controls (frequency: 0.41) (Choi_2007_PMID:12956637). The variant was also identified in a case report of an individual with suspected plasma cell neoplasm (Peterson_2019_PMID:31320253). The variant was identified in dbSNP (ID: rs17336800), ClinVar (classified as benign by Invitae) and LOVD 3.0, but was not identified in Cosmic. The variant was identified in control databases in 2092 of 267912 chromosomes (14 homozygous) at a frequency of 0.007809 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 348 of 24930 chromosomes (freq: 0.01396), European (non-Finnish) in 1370 of 117988 chromosomes (freq: 0.01161), Other in 75 of 6696 chromosomes (freq: 0.0112), Latino in 163 of 35096 chromosomes (freq: 0.004644), Ashkenazi Jewish in 24 of 9852 chromosomes (freq: 0.002436), South Asian in 67 of 30502 chromosomes (freq: 0.002197) and African in 45 of 23606 chromosomes (freq: 0.001906), but was not observed in the East Asian population. The p.Gly503Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Jul 26, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EGFR-related lung cancer

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Oct 28, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.6

(source)

DANN

Benign

0.44

PhyloP100

-0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over