Abstract

Background

We report the first case of a missense variant in the APC gene that interrupts splicing by creating a new cryptic acceptor site. The variant, c.289G>A, p.(Gly97Arg), is located in exon 3, and qualitative and semi-quantitative RNA splicing analysis reveal that the variant results in skipping of the last 70 nucleotides of the exon, which leads to the introduction of a frameshift and a premature stop codon.

Case presentation

The variant was detected in two, apparently unrelated, Danish families with an accumulation of colorectal cancers, colonic adenomas and other cancers. The families both have an attenuated familial adenomatous polyposis phenotype, which is consistent with the association of pathogenic variants in the 5′ end of the gene.

One variant-carrier also had Caroli Disease and a Caroli Disease associated hepatic mucinous cystadenocarcinoma. This is the first description of a person with both Caroli Disease and a pathogenic APC variant, and although the APC variant is not known to be connected to the development of the hepatic malformations in Caroli Disease, it remains unclear whether the variant could have contributed to the carcinogenesis of the liver tumour.

Conclusions

Based on functional and co-segregation data we classify the APC c.289G>A, p.(Gly97Arg) variant as pathogenic (class 5). Our findings emphasize the importance of a functional evaluation of missense variants although located far from the exon-intron boundaries.

Details

Title
A rare missense variant in APC interrupts splicing and causes AFAP in two Danish families
Author
Djursby, Malene; Wadt, Karin; Frederiksen, Jane Hübertz; Majbritt Busk Madsen; Berchtold, Lukas Adrian; Jane Preuss Hasselby; Willemoe, Gro Linno; Hansen, Thomas v O; Gerdes, Anne-Marie
Pages
1-6
Section
Case report
Publication year
2020
Publication date
2020
Publisher
BioMed Central
ISSN
17312302
e-ISSN
18974287
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2391476110
Copyright
© 2020. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.