Updated recommendation for the benign stand-alone ACMG/AMP criterion
Updated recommendation for the benign stand-alone ACMG/AMP criterion
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DOI：
10.1002/humu.23642
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发表时间：
2018-11-01
期刊：
影响因子：
3.9
通讯作者：
Biesecker, Leslie G.
中科院分区：
文献类型：
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作者：
Ghosh, Rajarshi;Harrison, Steven M.;Biesecker, Leslie G.
临床基因组资源（ClinGen）序列变异解释工作组着手完善美国医学遗传学和基因组学学院和分子病理学家协会（ACMG/AMP）变异致病性建议的独立规则BA1（小等位基因频率[MAF] bb0 0.05为良性），阐明如何使用该规则并指定一组应豁免该规则的变异。我们交叉参考了ClinVar和Exome Aggregation Consortium的数据，以确定具有合理致病性的变异，并且该变异存在于一个或多个种群数据集中，MAF为0.05。我们在这些数据集中发现了9个这样的变体，这些变体可能不是良性的。ACMG/AMP标准应用于这些变异，导致4种致病变异和5种不确定意义的变异。我们通过澄清用于描述其使用的术语、建议使用哪些数据库以及对该规则所做的假设，对良性规则BA1进行了改进。我们也发现了9个变异的初步列表，尽管这些变异的MAF很高，但它们有一些致病性的证据。我们指定了个人可以向ClinGen申请修改变异特异性断言的程序，以及专家在为特定基因设置较低的BA1阈值时应使用的标准。
The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group set out to refine the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG/AMP) variant pathogenicity recommendations for stand-alone rule BA1 (a variant with minor allele frequency [MAF] > 0.05 is benign), by clarifying how it should be used and specifying a set of variants that should be exempted from this rule. We cross-referenced ClinVar and Exome Aggregation Consortium data to identify variants for which there was a plausible argument for pathogenicity and the variant exists in one or more population data sets at MAF > 0.05. We identified nine such variants that were present in these data sets that may not be benign. The ACMG/AMP criteria were applied to these variants that resulted in four pathogenic and five variants of uncertain significance. We have refined benign rule BA1 by clarifying terms used to describe its use, which databases we recommend using, and assumptions made about this rule. We also recognized an initial list of nine variants for which there was some evidence of pathogenicity even though the MAF was high for these variants. We specify processes whereby individuals can petition ClinGen for amendments to our variant-specific assertions and the criteria experts should use when setting a numerically lower threshold for BA1 for specific genes.