Published online before print February 5, 2009

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Journal of Molecular Diagnostics 2009, Vol. 11, No. 2
Copyright © 2009 American Society for Investigative Pathology & Association for Molecular Pathology
DOI: 10.2353/jmoldx.2009.080129

Analysis of Rare APC Variants at the mRNA Level

Six Pathogenic Mutations and Literature Review

Astrid Kaufmann^*, Stefanie Vogt^*, Siegfried Uhlhaas^*, Dietlinde Stienen^*, Ingo Kurth, Horst Hameister, Elisabeth Mangold^*, Judith Kötting, Elke Kaminsky^¶, Peter Propping^*, Waltraut Friedl^* and Stefan Aretz^*

From the Institute of Human Genetics, * University Hospital of Bonn, Bonn; the Institute of Human Genetics, University Hospital of Hamburg-Eppendorf, Hamburg; the Institute of Human Genetics, University Hospital of Ulm, Ulm; the Department of Human Genetics, Ruhr-University Bochum, Bochum; and the Praxis für Humangenetik, ^¶ Hamburg, Germany

In monogenic disorders, the functional evaluation of rare, unclassified variants helps to assess their pathogenic relevance and can improve differential diagnosis and predictive testing. We characterized six rare APC variants in patients with familial adenomatous polyposis at the mRNA level. APC variants c.531 + 5G>C and c.532-8G>A in intron 4, c.1409-2_1409delAGG in intron 10, c.1548G>A in exon 11, and a large duplication of exons 10 and 11 result in a premature stop codon attributable to aberrant transcripts whereas the variant c.1742A>G leads to the in-frame deletion of exon 13 and results in the removal of a functional motif. Mutation c.1548G>A was detected in the index patient but not in his affected father, suggesting mutational mosaicism. A literature review shows that most of the rare APC variants detected by routine diagnostics and further analyzed at the transcript level were evaluated as pathogenic. The majority of rare APC variants, particularly those located close to exon-intron boundaries, could be classified as pathogenic because of aberrant splicing. Our study shows that the characterization of rare variants at the mRNA level is crucial for the evaluation of pathogenicity and underlying mutational mechanisms, and could lead to better treatment modalities.