Pathogenic mutations and rare variants of the APC gene identified in 75 Belgian patients with familial adenomatous polyposis by fluorescent enzymatic mutation detection (EMD)

Abstract

Familial adenomatous polyposis (FAP) is a dominant inherited colorectal cancer syndrome which is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Enzymatic mutation detection (EMD) has potential advantages over the standard protein truncation test (PTT) that is currently used in screening the APC gene for mutations. First we wanted to validate the EMD technique in comparison to PTT. Secondly, we wanted to develop an efficient working protocol for EMD screening of APC. Seventy-five unrelated patients were screened for mutations. All mutations that had previously been detected by PTT were also identified by EMD; the sizes of the cleavage fragments were as expected according to the position of the mutations within the amplicons. A new screening strategy based on EMD allows the analysis of the APC gene in 31 overlapping PCR fragments. In total, EMD efficiently detected the 26 truncating mutations in this series. In addition, two rare variants were also detected: the first is the typical Ashkenazi missense mutation I1307K while the second variant, E1317Q, has been identifed in Belgian patients and controls, and should no longer be considered as a pathogenic mutation, but rather classified as a polymorphism.

Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): A review of the literature

“…This observation was confirmed by studies of large numbers of patients [26,27]. The majority of germline mutations of the APC gene which cause the intermediate phenotype are located between codon 157 (exon 4) and codon 1595 (exon 15), excluding the mutation cluster region (MCR), where the profuse phenotype is found [13,22,27,28,30,31].…”

Next‐generation sequencing improves the diagnosis of thyroid FNA specimens with indeterminate cytology

“…For five patients, more than one mutation was detected. Mutations in KIT (p.M541L), APC and ATM that have been reported in the literature as germline polymorphisms were detected in nine samples (three MNG, one thyroiditis, four adenomas and one MIFC) (Table ). To evaluate the added value of NGS, we classified the patients into two categories: ‘molecular test negative’ (including patients carrying germline polymorphisms, mutations of unknown clinical significance or no mutation); or ‘molecular test positive’ for patients carrying pathogenic mutations (Tables and ).…”

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in familial colorectal cancer

“…However variants of the APC gene have now been detected which cause a milder phenotype (i.e. fewer polyps, later onset of CRC) [3,4]. The prevalence of attenuated FAP remains a matter of conjecture and the significance of APC mutations in familial non-polyposis CRC is not clear.…”