rs147149347
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_005228.5(EGFR):c.2305G>A(p.Val769Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V769L) 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 Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EGFR | NM_005228.5 | c.2305G>A | p.Val769Met | missense_variant | 20/28 | ENST00000275493.7 | |
EGFR-AS1 | NR_047551.1 | n.1257C>T | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EGFR | ENST00000275493.7 | c.2305G>A | p.Val769Met | missense_variant | 20/28 | 1 | NM_005228.5 | P1 | |
EGFR-AS1 | ENST00000442411.2 | n.1285C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251102Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135792
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461834Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727226
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
Lung carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 27, 2013 | - - |
EGFR-related lung cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 769 of the EGFR protein (p.Val769Met). This variant is present in population databases (rs147149347, gnomAD 0.02%). This missense change has been observed in individual(s) with lung cancer (PMID: 32913967). ClinVar contains an entry for this variant (Variation ID: 208821). 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 not expected to disrupt EGFR protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EGFR function (PMID: 32913967). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 26, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at