| Summary: | Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene <i>APC</i>. To date, nearly 2000 <i>APC</i> mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant <i>APC</i> splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in <i>APC</i> exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature meta-analysis of <i>APC</i> splicing mutations. We found that 119 unique <i>APC</i> splicing mutations, including the one described here, have been reported in FAP patients, 69 of which have been characterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with four mutations causing skipping of exon 12 or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and five mutations leading to skipping of exon 5, 7, 8, or (partially) 9 with loss of regions not encompassing known functional domains. The <i>APC</i> splicing mutations causing skipping of exon 12 or 13 considered in this study cluster with the AFAP phenotype and reveal a potential molecular mechanism of pathogenesis in FAP disease.
|
|---|