Garrett Alice, Allen Sophie, Durkie Miranda, Burghel George J, Robinson Rachel, Callaway Alison, Field Joanne, Frugtniet Bethan, Palmer-Smith Sheila, Grant Jonathan, Pagan Judith, McDevitt Trudi, Rowlands Charlie F, McVeigh Terri, Hanson Helen, Turnbull Clare
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom; Department of Clinical Genetics, St George's University Hospitals NHS Foundation Trust, Tooting, London, United Kingdom.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Genet Med. 2025 Feb;27(2):101305. doi: 10.1016/j.gim.2024.101305. Epub 2024 Oct 24.
Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.
A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group working group.
CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data.
CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.
当前的做法是，对于给定癌症易感基因中可能致病/致病的变异，在报告和管理时就如同它们具有相同的外显率一样，尽管越来越多的证据表明风险关联存在变异间的变异性。使用现有的变异解读方法（主要基于完全外显率模型），那些怀疑外显率降低的变异可能会被不一致地分类和/或被归类为意义未明的变异。我们旨在为英国癌症变异解读小组（CanVIG-UK）多学科网络内的此类变异制定一种全国性的共识方法。
在CanVIG-UK月度会议期间及会议之间，针对各种可能表明外显率降低的情况进行了一系列调查和实时投票。这些为CanVIG-UK指导与咨询小组工作组对降低外显率变异进行分类的框架的迭代开发提供了信息。
针对以下变异制定了CanVIG-UK对2015年美国医学遗传学与基因组学学会/美国病理学家协会（ACMG/AMP）变异解读框架的修订建议：（A）有确凿证据表明外显率降低效应大小（例如，来自病例对照或家系分离数据）的变异，以及（B）从较弱/可能不一致的观察数据推断出外显率降低效应的变异。
CanVIG-UK提出了一个对高外显率基因中降低外显率变异进行分类的框架。这些原则虽然是为癌症易感基因制定的，但可能适用于其他临床情况。
