ACMG/AMP对BRCA1错义变异的解读:基于结构的评分增加了PP3/BP4计算证据的证据强度粒度。

ACMG/AMP interpretation of BRCA1 missense variants: Structure-informed scores add evidence strength granularity to the PP3/BP4 computational evidence.

作者信息

Ramadane-Morchadi Lobna, Rotenberg Nitsan, Esteban-Sánchez Ada, Fortuno Cristina, Gómez-Sanz Alicia, Varga Matthew J, Chamberlin Adam, Richardson Marcy E, Michailidou Kyriaki, Pérez-Segura Pedro, Spurdle Amanda B, de la Hoya Miguel

机构信息

Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), 28040 Madrid, Spain.

University of Queensland, Brisbane, QLD, Australia; Molecular Cancer Epidemiology Laboratory, QIMR Berghofer MRI, Herston, QLD 4006, Australia.

出版信息

Am J Hum Genet. 2025 May 1;112(5):993-1002. doi: 10.1016/j.ajhg.2024.12.011. Epub 2025 Apr 14.

Abstract

Classification of missense variants is challenging. Lacking compelling clinical and/or functional data, ACMG/AMP lines of evidence are restricted to PM2 (rarity code applied at supporting level) and PP3/BP4 (computational evidence based mostly on multiple-sequence-alignment conservation tools). Currently, the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel uses BayesDel to apply PP3/BP4 to missense variants located in the BRCA1 RING/BRCT domains. The ACMG/AMP framework does not refer explicitly to protein structure as a putative source of pathogenic/benign evidence. Here, we tested the value of incorporating structure-based evidence such as relative solvent accessibility (RSA), folding stability (ΔΔG), and/or AlphaMissense pathogenicity to the classification of BRCA1 missense variants. We used MAVE functional scores as proxies for pathogenicity/benignity. We computed RSA and FoldX5.0 ΔΔG predictions using as alternative input templates for either PDB files or AlphaFold2 models, and we retrieved pre-computed AlphaMissense and BayesDel scores. We calculated likelihood ratios toward pathogenicity/benignity provided by the tools (individually or combined). We performed a clinical validation of major findings using the large-scale BRIDGES case-control dataset. AlphaMissense outperforms ΔΔG and BayesDel, providing similar PP3/BP4 evidence strengths with lower rate of variants in the uninformative score range. AlphaMissense combined with ΔΔG increases evidence strength granularity. AlphaFold2 models perform well as input templates for ΔΔG predictions. Regardless of the tool, BP4 (but not PP3) is highly dependent on RSA, with benignity evidence provided only to variants targeting buried or partially buried residues (RSA ≤ 60%). Stratification by functional domain did not reveal major differences. In brief, structure-based analysis improves PP3/BP4 assessment, uncovering a relevant role for RSA.

摘要

错义变异的分类具有挑战性。由于缺乏令人信服的临床和/或功能数据,美国医学遗传学与基因组学学会(ACMG)/分子病理学会(AMP)的证据等级仅限于PM2(支持级别应用的罕见性代码)和PP3/BP4(主要基于多序列比对保守性工具的计算证据)。目前,临床基因组学ENIGMA BRCA1/2变异管理专家小组使用BayesDel将PP3/BP4应用于位于BRCA1 RING/BRCT结构域的错义变异。ACMG/AMP框架没有明确将蛋白质结构作为致病/良性证据的推定来源。在此,我们测试了纳入基于结构的证据(如相对溶剂可及性(RSA)、折叠稳定性(ΔΔG)和/或AlphaMissense致病性)对BRCA1错义变异分类的价值。我们使用MAVE功能评分作为致病性/良性的代理指标。我们使用PDB文件或AlphaFold2模型作为替代输入模板计算RSA和FoldX5.0 ΔΔG预测,并检索预先计算的AlphaMissense和BayesDel评分。我们计算了这些工具单独或组合提供的针对致病性/良性的似然比。我们使用大规模BRIDGES病例对照数据集对主要发现进行了临床验证。AlphaMissense优于ΔΔG和BayesDel,在信息不丰富的评分范围内提供相似的PP3/BP4证据强度且变异率更低。AlphaMissense与ΔΔG相结合增加了证据强度的粒度。AlphaFold2模型作为ΔΔG预测的输入模板表现良好。无论使用何种工具,BP4(而非PP3)高度依赖RSA,仅向靶向埋藏或部分埋藏残基(RSA≤60%)的变异提供良性证据。按功能结构域分层未发现重大差异。简而言之,基于结构的分析改善了PP3/BP4评估,揭示了RSA的相关作用。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索