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Editor–Germline mutations of the adenomatous polyposis coli (APC) tumour suppressor gene result in the hereditary colorectal cancer syndrome familial adenomatous polyposis (FAP). Almost all APC mutations that have been identified are single nucleotide alterations, small insertions, or deletions that would cause a truncated APC protein.1Mutations causing amino acid changes in the APC protein have also been reported, but the association of these APCvariants with the FAP phenotype is sometimes unclear.
In a recent issue of this journal, a homozygous single base substitution involving an A to T transversion at codon 1822 of theAPC gene was reported as probably pathological in one FAP patient and two non-FAP patients.2
This double substitution causes an amino acid change (aspartic acid to valine) in the middle of the β-catenin down regulation domain of the APC protein and was the only genetic alteration found in the three aforementioned patients. A whole APC allele deletion was not proven in the samples, but dismissed by the authors as the patients did not exhibit the classical FAP phenotype that would be expected in patients with whole deletions. In an assay carried out on 45 normal subjects, Wallis et al 2 did not observe any homozygous changes at codon 1822.
We have found the heterozygous genotype Asp1822Val in the affected members of four FAP families out of 17 analysed in Spain and the homozygous nucleotide substitution was found in one of them. Surprisingly, the affected members of one of these five families carried another germline mutation in the APCgene (Ser2621Cys).3 These observations suggest that the common Asp1822Val alteration could be a lower penetrant allele that increases the risk of developing colorectal cancer.
To assess the risk of this APC allelic variant in …