title: Analysis of rare APC variants at the mRNA level: six pathogenic mutations and literature review.
abstract: 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.
authors.affiliation: Institute of Human Genetics, Bonn, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kaufmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Vogt
authors.forename: Siegfried
authors.initials: S
authors.lastname: Uhlhaas
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Stienen
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.forename: Horst
authors.initials: H
authors.lastname: Hameister
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Judith
authors.initials: J
authors.lastname: Kötting
authors.forename: Elke
authors.initials: E
authors.lastname: Kaminsky
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Waltraut
authors.initials: W
authors.lastname: Friedl
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D017491:Genes, APC; D006801:Humans; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics
chemical_list: D012333:RNA, Messenger