Evaluation of ACMG/AMP guidelines for classifying APC variants in Korean patients with suspected familial adenomatous polyposis.

backgroundAPC is the most frequently mutated gene in familial adenomatous polyposis (FAP). Recent advancements in sequencing technologies and the introduction of the 2024 APC-specific ACMG/AMP variant classification guidelines have reshaped the diagnostic landscape for hereditary polyposis syndromes.

methodsWe retrospectively reviewed APC variant data from 425 Korean patients clinically suspected of FAP between 2006 and 2020. Genetic testing included direct sequencing, targeted next-generation sequencing (NGS), multiplex ligation-dependent probe amplification, and mutant enrichment with 3'-modified oligonucleotide PCR. Variants were reclassified using the 2024 APC-specific ACMG/AMP criteria.

resultsPathogenic or likely pathogenic APC variants were detected in 166 of 425 patients (39.1%). Twenty-one novel truncating mutations were identified. The application of the 2024 APC-specific ACMG/AMP criteria led to the reclassification of 13 variants, with 2 pathogenic or likely pathogenic and 7 likely benign. Nine patients showed evidence of APC mosaicism.

conclusionThis is the first large-scale study to evaluate the clinical utility of the 2024 APC-specific ACMG/AMP variant interpretation guidelines, enabling the reclassification of previously designated variants of uncertain significance into more definitive categories. The detection of mosaic variants emphasizes the need for higher sequencing depth. Our results support the integration of NGS and further diagnostic evaluation into APC variant testing.