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

ABSTRACT 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.