In a series of 15 hepatic adenomas resected from premenopausal women, direct sequencing of the APC mutational cluster region found no APC mutations overall, but one case (Case 9) carried a base-pair change at codon 1454 (AAA to GAA) producing an amino acid substitution, lysine to glutamate (reported in the text as lysine to glutamine). This change was present in both the patient's normal liver and the adenoma and was therefore interpreted as a polymorphism of unknown significance; the patient had no clinical evidence of a colonic polyposis syndrome. Codon 1454 noted occasionally affected by insertions/deletions but no missense mutations in the cited Thierry Soussi APC database.

✓ Names this variant — characterised directly

This paper explicitly names the exact variant K1454E. It was identified as a rare (MAF <2%) inherited nonsynonymous APC variant within the beta-catenin down-regulating domain, occurring once among non-FAP/non-MAP colorectal adenoma (CRA) patients recorded as having multiple CRAs of unknown number (Table 1), and twice among the 969 healthy controls (Table 1). The authors list K1454E as one of five variants detected in both the patient cohort and the control group. K1454E was not among the 16 nonsynonymous variants functionally assayed by beta-catenin-regulated transcription (CRT), so no variant-specific CRT result is reported for it. The paper's overall finding relevant to the gene is that rare nonsynonymous APC variants are overrepresented in non-FAP non-MAP CRA patients (81/480, 16.9% vs 20/211 FAP/MAP, P=0.0113), including specifically within the beta-catenin down-regulating domain compared with controls (32/480 vs 37/969, P=0.0166), supporting a low-penetrance predisposition role.

✓ Names this variant — characterised directly

This paper directly reports the APC c.4360A>G (p.Lys1454Glu / K1454E) substitution as a somatic missense mutation in invasive urothelial (bladder) carcinoma. Sequencing of the APC mutation cluster region (codons 1260-1541) in tumor tissue from 70 patients with muscle-invasive disease identified single amino-acid substitutions in 9/70 (13%) tumors and frameshift deletions in 2/70 (3%). The identical AAA>GAA change at codon 1454 (Lys>Glu) was found in three separate patients (patients 5, 7 and 8), making it the most recurrent missense change in the series, and was confirmed as somatic by absence in the matched normal urothelial tissue. All missense substitutions, including codon 1454, were located between or adjacent to the 20-amino-acid repeats that constitute the beta-catenin binding sites; the authors state all missense mutations identified were novel and differ from the usual (chain-terminating) colorectal cancer spectrum, and speculate that such substitutions may alter APC 3-D conformation and its affinity for beta-catenin. Clinically, APC somatic mutations were associated with significantly shorter disease-specific overall survival (18 vs 60 months, p=0.02), and in multivariate analysis the presence of a somatic APC mutation or beta-catenin nuclear accumulation was an independent predictor of worse survival (p=0.048). No APC mutations were found in upper urinary tract tumors (all mutations were in bladder tumors). This is a somatic-tumor study with no germline classification data or functional assay for this variant.

✓ Names this variant — characterised directly