Landmark report (Lynch et al., NEJM 2004) linking somatic EGFR tyrosine kinase domain mutations to gefitinib responsiveness in NSCLC. It explicitly identifies the L858R variant (substitution of G for T at nucleotide 2573, exon 21) in two gefitinib-responsive patients (Patients 5 and 6) among 8 mutation-positive of 9 responders. Both L858R tumors were heterozygous with wild-type matched normal tissue (somatic origin). The paper interprets the recurrent somatic mutations as conferring an additive, dominant gain of function clustered near the ATP cleft of the tyrosine kinase domain, and provides functional assay data (EGF-induced activation doubled/tripled vs wild-type and sustained up to 3 hours; gefitinib 50% inhibition at ~0.015 uM vs 0.1 uM for wild-type). For this group's criteria: at codon 858 only L858R is described (L861Q is at codon 861), so no alternate-nucleotide or alternate-missense comparator at residue 858 is reported.

✓ Names this variant — characterised directly

Paez et al., Science 2004: explicitly describes the EGFR L858R mutation (CTG>CGG, heterozygous, somatic) - the same variant as c.2573T>G p.(Leu858Arg). L858R was found in 3 of 16 EGFR-mutant unselected NSCLC tumors (all lung adenocarcinomas, absent from matched normal tissue). The paper states these mutations are located in the GXGXXG motif of the nucleotide triphosphate binding domain (P-loop) and adjacent to the highly conserved DFG motif in the activation loop, respectively, and that the mutated residues are nearly invariant in all protein kinases (analogous B-Raf residues G463 and L596 are somatically mutated in cancer). Functional data: the H3255 lung adenocarcinoma cell line carries L858R and was ~50x more sensitive to gefitinib than EGFR wild-type lines (IC50 40 nM). For this group: no alternate nucleotide or alternate amino-acid change at codon 858 is reported.

✓ Names this variant — characterised directly

Pao et al., PNAS 2004: explicitly reports the EGFR c.2573T>G (L858R) mutation in multiple lung cancer cohorts (gefitinib- and erlotinib-sensitive tumors; untreated never-smoker adenocarcinomas 7/15 mutated with 5 L858R; only 4/81 smoker NSCLCs mutated, all L858R). The paper states L858R 'occurs adjacent to the highly conserved DFG motif (amino acids 855-857) in the activation loop of the kinase' and that L858R was one of two mutation hotspots, accounting for 20/49 (41%) of reported TK-domain hotspot mutations (with exon 19 deletions). Functional data: in 293T cells, L858R EGFR autophosphorylation similar to wild-type but inhibited at approximately 10-fold lower gefitinib/erlotinib concentrations. Matched normal tissue showed wild-type sequence (somatic origin). For this group: only the nucleotide-2573 T>G change at codon 858 is described; the same change was 'previously detected in NSCLCs' (recurrence of the identical change, not an alternate-nucleotide comparator).

✓ Names this variant — characterised directly

The paper classifies EGFR L858R as a 'classical' EGFR mutation, defined as such in the Methods and used throughout as the TKI-sensitive reference group against which atypical mutations are compared. It states that patients with classical EGFR mutations (L858R or exon 19 deletions) show marked improvements in clinical outcomes with first-, second- or third-generation TKIs, and in the authors' own multi-database cohort (16,715 EGFR-mutant NSCLC patients), patients with classical mutations had a longer time to treatment failure on EGFR TKIs than patients with atypical mutations (HR=1.8, P<0.0001; classical n=245 versus atypical n=109). No new functional assay or prevalence data specific to L858R itself is presented; L858R serves as the sensitive classical comparator. The paper additionally reports three patients with NSCLC containing EGFR L858R who received first-line osimertinib and at progression each acquired PACC-class resistance mutations (two acquired L718V, one acquired V765L and C797S); all three then derived clinical benefit (stable disease and tumour shrinkage) from second-generation TKI treatment.

✓ Names this variant — characterised directly