ENIGMA 研究联盟开发并应用方法来确定遗传性乳腺癌和卵巢癌基因变异的临床意义。 ENIGMA BRCA1/2 分类小组于 2015 年作为 ClinGen 外部专家小组成立，现已发展成为 ClinGen 内部变体管理专家小组 (VCEP)，以与食品和药物管理局认可的 ClinVar 贡献流程保持一致。 VCEP 审查了美国医学遗传学和基因组学学院/分子病理学协会 (ACMG/AMP) 分类标准与解释 BRCA1 和 BRCA2 变异的相关性。使用统计方法来校准不同数据类型的证据强度。对 40 种型号的试点规范进行了测试，并修订了文档以使其清晰且易于使用。 13 个证据代码的原始标准描述被认为不适用或与其他标准重叠。八个代码的使用场景得到了扩展或重新调整。广泛的分析和/或数据审查为所有代码提供了规格描述和权重。规范应用于具有预先存在的 ClinVar 分类的试点变异，如下：13 个不确定意义或冲突，14 个致病和/或可能致病，以及 13 个良性和/或可能良性。检查 11/13 不确定意义或冲突变体的已解决分类，并保留或提高剩余变体分类的置信度。现有 ENIGMA 研究分类流程与 ACMG/AMP 分类指南的一致性凸显了研究流程和基线 ACMG/AMP 标准中的一些差距。证据强度的校准是证明不同数据类型对于基因特定应用的效用和强度的关键。基因特异性标准证明了对于改进 BRCA1 和 BRCA2 变异的 ACMG/AMP 对齐分类的价值。版权所有 © 2024 美国人类遗传学会。由爱思唯尔公司出版。保留所有权利。

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.