Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2_SupportingPM5PP3_Strong
The NM_005228(EGFR):c.2155G>A(p.Gly719Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G719C) has been classified as Likely pathogenic.
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
GnomAD3 genomesCov.: 33
Submissions by phenotype
Non-small cell lung carcinoma
|Pathogenic, no assertion criteria provided||literature only||Database of Curated Mutations (DoCM)||Jul 14, 2015||- -|
EGFR-related lung cancer
|Uncertain significance, criteria provided, single submitter||clinical testing||Invitae||Aug 16, 2021||This sequence change replaces glycine with serine at codon 719 of the EGFR protein (p.Gly719Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant is a common somatic change in non-small cell lung cancer (NSCLC) (PMID: 29100434, 25061320, 23468066, 24039832). While this variant has been reported in the literature, it has not been reported in the germline of individuals with EGFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 16612). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -|
Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in, somatic
|drug response, no assertion criteria provided||literature only||OMIM||Jun 04, 2004||- -|
Tyrosine kinase inhibitor response
|drug response, criteria provided, single submitter||clinical testing||Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine||Apr 20, 2012||- Responsive|
Neoplasm of the large intestine
|not provided, no assertion provided||literature only||Database of Curated Mutations (DoCM)||Mar 10, 2016||- -|
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