Evaluation of MLH1 variants of unclear significance
Evaluation of MLH1 variants of unclear significance
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DOI：
10.1002/gcc.22536
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发表时间：
2018-07-01
影响因子：
3.7
通讯作者：
Plotz, Guido
中科院分区：
文献类型：
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作者：
Koeger, Nicole;Paulsen, Lea;Plotz, Guido
MLH1基因的失活突变导致癌症易感性Lynch综合征，但对于小的编码基因变异，人们大多不清楚它们是否失活。在南美结直肠癌（CRC）患者中发现了9个这样的MLH1变异（p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro），并且没有证据表明大多数这些变异具有致病性或中性。因此，我们对变异蛋白进行了生化实验室测试，并将结果与蛋白质在结构和保护方面的计算机预测结果进行了比较。此外，我们还收集了所有可获得的家庭临床资料，以得出其致病潜力的结论，以便于患病家庭的临床诊断。我们提供的证据表明，其中四个改变是Lynch综合征的病因，四个可能是中性的，一个显示出受损的活动，目前还不能根据其致病潜力进行分类。这项工作表明，生化测试，由一致的进化和结构信息证实，可以可靠地分类不确定的变异，当其他数据不足。
Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.