# Deciphering the Causative Role of a Novel APC Gene Variant in Attenuated Familial Adenomatous Polyposis Using Germline DNA-RNA Paired Testing

## TL;DR

This study identifies a new APC gene variant causing a milder form of a genetic disorder and shows how DNA-RNA testing helps understand its effects.

## Contribution

The study demonstrates the value of DNA-RNA paired testing in characterizing a novel APC variant's dual transcriptional effects in AFAP.

## Key findings

- The APC variant produces two transcripts: one with a truncated protein and another with a 26-amino acid deletion.
- The transcript lacking exon 12 is more abundant due to degradation of the other transcript via nonsense-mediated decay.
- Combined DNA-RNA testing improves classification of APC variants and genotype-phenotype correlations in FAP.

## Abstract

Background/Objectives: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by pathogenic variants in the adenomatous polyposis coli (APC) gene. Its attenuated form (AFAP) is characterized by fewer colorectal polyps and later onset of colorectal cancer. We aimed to characterize the molecular effects of a novel APC gene variant (NM_000038.6: c.1620_1624delinsT) identified in a patient with AFAP. Methods: A 56-year-old man with the AFAP phenotype underwent germline testing via a multigene NGS panel, which identified a novel APC gene variant (NM_000038.6: c.1620_1624delinsT). In silico analyses predicted disruption of the canonical donor splice site and a frameshift followed by the introduction of a premature stop codon. The transcriptional impact of the identified APC gene variant was investigated by mRNA analysis. Results: mRNA analysis revealed two distinct APC transcripts: the first transcript led to a truncated protein (p.Leu540PhefsTer8), and the second transcript lacked exon 12, resulting in an in-frame 26 amino acid deletion of APC protein (p.Ala517_Gly542del). The transcript lacking exon 12 was more abundant than the transcript with a premature stop codon, likely due to degradation through nonsense-mediated decay. Conclusions: The APC gene variant (NM_000038.6: c.1620_1624delinsT) exhibits a dual transcriptional effect, revealing its pathogenic role in AFAP. This study highlights the diagnostic value of combined DNA–RNA germline testing for improving the clinical classification of novel APC gene variants and their genotype–phenotype correlations in FAP.