Clinical Utility of Expanded Multigene Testing in Hereditary Polyposis Syndromes: Diagnostic Yield and Functional Characterization of Clinically Relevant Variants

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Background/Aim: Hereditary polyposis syndromes comprise a genetically heterogeneous group of disorders characterized by the development of multiple gastrointestinal polyps and an increased risk of colorectal cancer (CRC). Although pathogenic variants in APC and MUTYH account for a substantial proportion of cases, the molecular basis remains unresolved in many patients, supporting the implementation of expanded multigene testing strategies. Patients and Methods: We evaluated 50 unrelated patients with suspected hereditary polyposis using next-generation sequencing (NGS) and a comprehensive 101-gene hereditary cancer panel. Variants were classified according to ACMG/AMP recommendations and disease-specific ClinGen Variant Curation Expert Panel specifications whenever available. Genotype–phenotype correlations were assessed, and functional RNA analysis was performed for a selected splice-site variant. Results: Pathogenic or likely pathogenic germline variants were identified in 14 of 50 patients, yielding a diagnostic rate of 28%. A total of 17 clinically relevant variants were detected across eight genes. APC and MUTYH accounted for 64.7% (11/17) of all identified variants, confirming their predominant role in hereditary polyposis. Variants were also identified in other polyposis-associated genes (SMAD4 and PTEN) and in four additional hereditary cancer predisposition genes (ATM, CDKN2A, CHEK2, and FANCM). Functional RNA studies demonstrated that the APC c.220+3A>T splice-site variant causes complete exon 3 skipping, supporting its reclassification as likely pathogenic. In addition, a novel pathogenic FANCM frameshift variant not previously reported in ClinVar was identified. Ten variants of uncertain significance were detected and are reported as supplementary findings. Overall, the results demonstrate substantial molecular heterogeneity among patients with hereditary polyposis. Conclusion: Expanded multigene panel testing improves the molecular characterization of hereditary polyposis syndromes and facilitates the identification of clinically actionable variants in both established polyposis-associated genes and other hereditary cancer predisposition genes. The detection of variants beyond APC and MUTYH, together with the functional characterization of clinically relevant variants, highlights the value of comprehensive germline testing for improving diagnosis, risk assessment, surveillance strategies, and genetic counseling in patients with suspected hereditary polyposis.

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