Su Yang, Li Xiang, Reva Boris, Antipin Yevgeniy, Schultz Nikolaus, de Bruijn Ino, Sander Chris
Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
bioRxiv. 2025 Aug 12:2025.08.10.669566. doi: 10.1101/2025.08.10.669566.
MutationAssessor (MA) helps researchers evaluate the likely functional impact of somatic and germline mutations in cancer. It provides an evolution-based functional impact score (FIS) to classify mutations based on their likely effect on protein function. FIS scores are based on analysis of patterns of conservation in protein families (conserved residues) and subfamilies (specificity residues). In this new version (r4) we have (1) refined the combinatorial entropy analysis of conservation patterns, (2) recalculated full-length protein multiple sequence alignments covering a larger fraction of human proteins and making use of the explosive growth of protein sequence data, (3) compared predicted functional impact with the pathogenic-benign classification of sequence variants in curated knowledge bases, such as ClinVar, (4) observed the inverse relationship between predicted high functional impact and variant frequency in germline genome sequences and (5) explore the evaluation of switch-of-function mutational effects. Functional impact of ~4 million somatic amino-acid changing mutations across more than 320K human tumor samples are now available in the widely used cBioPortal for Cancer Genomics.
突变评估工具（MA）可帮助研究人员评估癌症中体细胞突变和种系突变可能产生的功能影响。它提供了一个基于进化的功能影响评分（FIS），以便根据突变对蛋白质功能的可能影响对其进行分类。FIS评分基于对蛋白质家族（保守残基）和亚家族（特异性残基）中保守模式的分析。在这个新版本（r4）中，我们（1）改进了保守模式的组合熵分析，（2）重新计算了覆盖更大比例人类蛋白质的全长蛋白质多序列比对，并利用了蛋白质序列数据的爆炸式增长，（3）将预测的功能影响与诸如ClinVar等经过整理的知识库中序列变异的致病-良性分类进行比较，（4）观察到预测的高功能影响与种系基因组序列中变异频率之间的反比关系，以及（5）探索了功能转换突变效应的评估。现在，在广泛使用的癌症基因组学cBioPortal中，可以获取超过32万个人类肿瘤样本中约400万个体细胞氨基酸改变突变的功能影响。
