A rare missense variant in APC interrupts splicing and causes AFAP in two Danish families

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 semiquantitative 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.

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

“…The variant has previously been reported in a Chinese patient with mild FAP (Wang et al, 2019). The variant creates a cryptic acceptor splice site and interrupts normal splicing; this family and the results of the functional analyses have already been published (Djursby et al, 2020). Based on these data, we consider the APC c.289G>A variant likely pathogenic.…”

First Evidence of Familial Transmission of Hereditary Gastrointestinal Polyposis Associated with Germline APC Variant in Jack Russell Terriers

“…In humans, when germline variants likely associated with a certain disease are observed in patients, it is possible to examine their close relatives, such as parents and siblings, relatively easily to determine whether the disease is transmitted in association with the candidate DNA variant within the family. For example, while more than 3000 different germline APC variants causing FAP have been identified [ 17 ], novel pathogenic APC variants have still been discovered in recent studies in which examinations of family members were conventionally performed [ 18 , 19 , 20 , 21 ]. In contrast, it is challenging to trace the relatives of household dogs after disease onset.…”