Ritter D I, Badduke C, Doonanco K, Kang H C, Pesaran T, Ridd S, Sheen C, Farncombe K M, Giles R H, Luo M, Pipko N, Tsoi C T, McGoldrick K, Mighton C, Abu Kashabeh R H, Sanabria-Salas M C, Talab Y, Deka K B, Jacobs M F, Tuzlali E, Gallinger B, Griffith M, Krysiak K, Machado J, Maher E R, Tirosh A, Kim R H
Baylor College of Medicine and Texas Children's Hospital, Department of Pediatrics.
PreventionGenetics part of Exact Sciences, Marshfield, WI.
medRxiv. 2025 Aug 27:2025.08.25.25334371. doi: 10.1101/2025.08.25.25334371.
The Clinical Genome Resource (ClinGen) Von Hippel-Lindau (VHL) Variant Curation Expert Panel (VCEP) has created variant classification specifications tailored to the gene, including phenotype-driven and evidence-based criteria, somatic and germline mutational hotspots, functional and in-silico data.
Using the American College of Medical Genetics and Genomics (ACMG) guidance and the ClinGen Sequence Variant Interpretation (SVI) recommendations, the VCEP made substantial modifications to eight evidence codes (PVS1, PS3, PS4, PM1, BS2, BS3, BS4, BP5), while 14 had minor or no changes and 6 were not used (PM3, PP2, BP1, PP4, PP5/BP6). The VHL VCEP applied two literature sets of over >428 papers in Clinical Interpretations of Variants in Cancer (CIViC) and >8700 structured annotations using Hypothesis.
From 31 pilot variants, 15 remained pathogenic/likely pathogenic, 9 resolved to benign through the stand-alone benign evidence code and 7 variants with initial uncertain classifications, with many lacking additional literature, remained uncertain.
The versioned VHL VCEP specifications are publicly available in the ClinGen Criteria Specifications Registry and will enhance the transparency and consistency of variant classifications for this highly sequenced hereditary cancer gene.
临床基因组资源（ClinGen）的冯·希佩尔-林道（VHL）变异评估专家小组（VCEP）制定了针对该基因的变异分类规范，包括表型驱动和基于证据的标准、体细胞和种系突变热点、功能和计算机模拟数据。
VCEP依据美国医学遗传学与基因组学学会（ACMG）指南以及ClinGen序列变异解读（SVI）建议，对八个证据代码（PVS1、PS3、PS4、PM1、BS2、BS3、BS4、BP5）进行了重大修改，而14个证据代码有微小改动或未作更改，6个证据代码未被使用（PM3、PP2、BP1、PP4、PP5/BP6）。VHL VCEP应用了两组文献，一组来自《癌症变异的临床解读》（CIViC）中的428篇以上论文，另一组来自使用Hypothesis的8700多条结构化注释。
在31个试点变异中，15个仍为致病性/可能致病性，9个通过独立的良性证据代码判定为良性，7个初始分类不确定的变异（其中许多缺乏额外文献支持）仍不确定。
版本化的VHL VCEP规范可在ClinGen标准规范注册库中公开获取，将提高这个高测序遗传性癌症基因变异分类的透明度和一致性。
