Diagnostic Yield of Expanded Multigene Testing in Hereditary Polyposis Syndromes: Functional Characterization of Clinically Relevant Variants
4 affiliations
- 1Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), Valladolid, Spain
- 2Valladolid Health Research Institute (IBioVALL), Valladolid, Spain
- 3Unit of Genetic Counseling in Cancer, Complejo Hospitalario de Burgos, Burgos, Spain
- 4Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, Valladolid, Spain
Abstract
Background/Aim: Hereditary polyposis syndromes comprise a genetically heterogeneous group of disorders characterized by 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 use of expanded multigene testing.
Materials and Methods: Fifty unrelated patients with suspected hereditary polyposis were analyzed using next-generation sequencing (NGS) and a 101-gene hereditary cancer panel. Variants were classified according to ACMG/AMP recommendations and disease-specific ClinGen specifications when available. Functional RNA analysis was performed for a selected splice-site variant.
Results: Pathogenic or likely pathogenic variants were identified in 14/50 patients (overall detection rate: 28.0%), whereas variants in established polyposis-predisposition genes accounted for a diagnostic yield of 20.0% (10/50). Fourteen unique variants corresponding to 17 variant observations were identified across eight genes. APC and MUTYH accounted for 64.7% (11/17) of all variant observations. Variants were also detected 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 generates an aberrant transcript consistent with complete exon 3 skipping. In addition, the FANCM c.3911delA (p.Asn1304Ilefs*8) variant, not previously reported in ClinVar, was identified. Ten variants of uncertain significance were detected.
Conclusion: Expanded multigene panel testing identified pathogenic or likely pathogenic germline variants in 28.0% of patients with suspected hereditary polyposis, while established polyposis-predisposition genes accounted for a diagnostic yield of 20.0%. The marked molecular heterogeneity observed supports the value of comprehensive germline testing for molecular diagnosis and hereditary cancer risk characterization.
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BibTeX
@article{martin2026diagnostic,
title = {{Diagnostic Yield of Expanded Multigene Testing in Hereditary Polyposis Syndromes: Functional Characterization of Clinically Relevant Variants}},
author = {ELSA MORENO MARTÍN and MÓNICA ARRANZ-LEDO and ENRIQUE LASTRA ARAS and AMAYA OLAVERRI HERNÁNDEZ and RAQUEL FERREIRA ALONSO and LARA HERNÁNDEZ SANZ and NOEMÍ MARTÍNEZ MARTÍN and MAR INFANTE SANZ and MERCEDES DURÁN DOMÍNGUEZ},
journal = {Cancer Genomics \& Proteomics},
year = {2026},
month = oct,
doi = {10.21873/cgp.20619},
url = {https://doi.org/10.21873/cgp.20619},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Diagnostic Yield of Expanded Multigene Testing in Hereditary Polyposis Syndromes: Functional Characterization of Clinically Relevant Variants
AU - ELSA MORENO MARTÍN
AU - MÓNICA ARRANZ-LEDO
AU - ENRIQUE LASTRA ARAS
AU - AMAYA OLAVERRI HERNÁNDEZ
AU - RAQUEL FERREIRA ALONSO
AU - LARA HERNÁNDEZ SANZ
AU - NOEMÍ MARTÍNEZ MARTÍN
AU - MAR INFANTE SANZ
AU - MERCEDES DURÁN DOMÍNGUEZ
PY - 2026
DA - 2026/10/31
JO - Cancer Genomics & Proteomics
DO - 10.21873/cgp.20619
UR - https://doi.org/10.21873/cgp.20619
AB - Background/Aim: Hereditary polyposis syndromes comprise a genetically heterogeneous group of disorders characterized by 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 use of expanded multigene testing. Materials and Methods: Fifty unrelated patients with suspected hereditary polyposis were analyzed using next-generation sequencing (NGS) and a 101-gene hereditary cancer panel. Variants were classified according to ACMG/AMP recommendations and disease-specific ClinGen specifications when available. Functional RNA analysis was performed for a selected splice-site variant. Results: Pathogenic or likely pathogenic variants were identified in 14/50 patients (overall detection rate: 28.0%), whereas variants in established polyposis-predisposition genes accounted for a diagnostic yield of 20.0% (10/50). Fourteen unique variants corresponding to 17 variant observations were identified across eight genes. APC and MUTYH accounted for 64.7% (11/17) of all variant observations. Variants were also detected 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 generates an aberrant transcript consistent with complete exon 3 skipping. In addition, the FANCM c.3911delA (p.Asn1304Ilefs*8) variant, not previously reported in ClinVar, was identified. Ten variants of uncertain significance were detected. Conclusion: Expanded multigene panel testing identified pathogenic or likely pathogenic germline variants in 28.0% of patients with suspected hereditary polyposis, while established polyposis-predisposition genes accounted for a diagnostic yield of 20.0%. The marked molecular heterogeneity observed supports the value of comprehensive germline testing for molecular diagnosis and hereditary cancer risk characterization.
SN - 1109-6535
SN - 1790-6245
ER -