KRAS G12Y Causing a False-Positive KRAS G12C Result With an Indistinguishable PCR Pattern in Lung Adenocarcinoma

KRAS G12C is an actionable alteration in non-small cell lung cancer, making accurate molecular identification essential for treatment selection. A 61-year-old man with metastatic lung adenocarcinoma showed a KRAS G12C-positive reaction on the AmoyDx Pan Lung Cancer PCR Panel (AmoyDx PLC panel). After progression on first-line chemoimmunotherapy, sotorasib was administered, but progressive disease was observed at the first radiologic assessment. Subsequent NGS-based comprehensive genomic profiling of the same pretreatment FFPE block identified KRAS G12Y (c.34_35delinsTA; variant allele frequency, 25.8%), with no sequence reads supporting KRAS G12C. This prompted suspicion of a false-positive PCR result. Repeat AmoyDx PLC panel testing reproduced the G12C-positive reaction and testing of a KRAS G12Y plasmid likewise yielded a G12C-positive reaction without additional KRAS-associated signals, confirming cross-reactivity. KRAS G12Y can therefore mimic genuine KRAS G12C in mutation-specific PCR testing and may lead to inappropriate genotype-directed therapy.