rs144496976

chr7-55200352-G-Achr7-55200352-G-Cchr7-55200352-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4 BP6 BS1

The NM_005228.5(EGFR):c.2885G>A(p.Arg962His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,084 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R962C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 8.15

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_benign. Variant got -4 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity EGFR_HUMAN there are 56 pathogenic changes around while only 8 benign (88%) in NM_005228.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.4003565).
• BP6: Variant 7-55200352-G-A is Benign according to our data. Variant chr7-55200352-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134027.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00024 (351/1461884) while in subpopulation SAS AF= 0.000638 (55/86258). AF 95% confidence interval is 0.000503. There are 2 homozygotes in gnomad4_exome. There are 193 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.2885G>A	p.Arg962His	missense_variant	24/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2885G>A	p.Arg962His	missense_variant	24/28	1	NM_005228.5	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152080 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000282 AC: 71 AN: 251492 Hom.: 1 AF XY: 0.000316 AC XY: 43 AN XY: 135922

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000240 AC: 351 AN: 1461884 Hom.: 2 Cov.: 31 AF XY: 0.000265 AC XY: 193 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74396

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

EGFR-related lung cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 962 of the EGFR protein (p.Arg962His). This variant is present in population databases (rs144496976, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer, osteosarcoma, non-Hodgkin lymphoma, and nodular sclerosis Hodgkin lymphoma (PMID: 32191290, 34308104, 35264596). ClinVar contains an entry for this variant (Variation ID: 134027). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EGFR protein function with a positive predictive value of 80%. 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. -

EGFR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

The EGFR c.2885G>A variant is predicted to result in the amino acid substitution p.Arg962His. This variant has been reported in multiple individuals with breast cancer, osteosarcoma, and diffuse large B cell lymphoma (see for example, Table S3, Guindalini et al. 2022. PubMed ID: 35264596; Table S5, Mirabello et al. 2020. PubMed ID: 32191290; search 55268045 in Table S2, Kim et al. 2021. PubMed ID: 34308104). This variant is reported in 0.065% of alleles in individuals of South Asian descent in gnomAD. This variant has been classified as a variant of uncertain significance by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134027/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Apr 09, 2024

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;D;D
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Uncertain	0.084	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Uncertain	0.54
Sift	Benign	0.039	D;.;D
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.95	P;.;D
Vest4		0.67
MVP		0.81
MPC		1.6
ClinPred		0.17	T
GERP RS		5.6
Varity_R		0.59
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs144496976; hg19: chr7-55268045; COSMIC: COSV51838693;