Brief report: Clinical and Functional Characterization of Rare Germline and Somatic EGFR Variants in Three Patients with Non-Small Cell Lung Cancer

EGFR

Germline EGFR variants (p.(Gly719Ser), p.(Arg776His)) combined with a second somatic variant in cis, with oncogenic activity and afatinib sensitivity

Hereditary risk factors for non-small cell lung cancer (NSCLC) remain poorly understood, although rare germline EGFR and TP53 alterations have been reported. Within the German National Network for Genomic Medicine, germline whole genome sequencing (WGS) identified two germline EGFR variants, p.(Gly719Ser) and p.(Arg776His), in three patients with NSCLC, each carrying additional somatic variants forming compound variants. Structural modelling predicts that p.(Gly719Ser) and p.(Gly719Ala) stabilise the active kinase conformation, whereas p.(Ser768Ile), p.(Arg776His) and p.(Leu861Gln) destabilise the inactive conformation. In the Ba/F3 cell model, cis co-expression of the compound variants showed oncogenic activity and afatinib sensitivity. Two patients achieved a partial response to afatinib.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This work is a reminder that some EGFR variants seen in NSCLC are germline, with implications for family counselling. With three patients, however, the penetrance of p.(Gly719Ser) and p.(Arg776His) remains unknown, and the afatinib response reflects the cis compound variants rather than the germline variant alone. The main value is methodological: combining structural prediction and functional testing to interpret rare variants.

Analysis by Dr Thibaut Benquey