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 semi-quantitative 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.

中文翻译：

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APC 中一种罕见的错义变异会中断剪接并在两个丹麦家庭中导致 AFAP

背景 我们报告了 APC 基因中的第一个错义变体，它通过创建一个新的隐蔽受体位点来中断剪接。变体 c.289G>A, p.(Gly97Arg) 位于外显子 3，定性和半定量 RNA 剪接分析显示该变体导致外显子最后 70 个核苷酸的跳跃，从而导致引入移码和过早终止密码子。病例介绍 在两个明显不相关的丹麦家庭中发现了该变体，这些家庭患有结直肠癌、结肠腺瘤和其他癌症。这两个家族都具有减毒的家族性腺瘤性息肉病表型，这与基因 5' 端致病变异的关联是一致的。一名变异携带者还患有卡罗利病和卡罗利病相关的肝粘液性囊腺癌。这是对同时患有 Caroli 病和致病性 APC 变异的人的首次描述，虽然目前尚不知道 APC 变异与 Caroli 病肝脏畸形的发展有关，但尚不清楚该变异是否可能导致肝癌的致癌作用。结论 基于功能和共分离数据，我们将 APC c.289G>A, p.(Gly97Arg) 变体分类为致病性（5 类）。我们的研究结果强调了错义变体功能评估的重要性，尽管它远离外显子-内含子边界。尽管目前尚不清楚 APC 变体与 Caroli 病中肝脏畸形的发展有关，但尚不清楚该变体是否可能导致肝癌的发生。结论 基于功能和共分离数据，我们将 APC c.289G>A, p.(Gly97Arg) 变体分类为致病性（5 类）。我们的研究结果强调了错义变体功能评估的重要性，尽管它远离外显子-内含子边界。尽管目前尚不清楚 APC 变体与 Caroli 病中肝脏畸形的发展有关，但尚不清楚该变体是否可能导致肝癌的发生。结论 基于功能和共分离数据，我们将 APC c.289G>A, p.(Gly97Arg) 变体分类为致病性（5 类）。我们的研究结果强调了错义变体功能评估的重要性，尽管它远离外显子-内含子边界。