rs144496976
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4BP6BS1BS2
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
Consequence
NM_005228.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
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: 18AN: 152080Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000282 AC: 71AN: 251492Hom.: 1 AF XY: 0.000316 AC XY: 43AN XY: 135922
GnomAD4 exome AF: 0.000240 AC: 351AN: 1461884Hom.: 2 Cov.: 31 AF XY: 0.000265 AC XY: 193AN XY: 727240
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74396
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at