PDF(Pubmed)
Abstract：
Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.
The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.
We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles.
These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.
We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles.
These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
摘要：
目的：外显谱低端的遗传变异历来难以解释，因为它们的高人群频率超过了相关疾病的患病率。导致变异和疾病之间缺乏明确的隔离。目前，这些变体的分类存在很大差异，没有正式的分类框架被广泛采用。成立了临床基因组资源低渗透/风险等位基因工作组，以应对这些挑战并促进临床社区内的协调。
方法：此处介绍的工作是内部和社区Likert规模调查的产物，并结合工作组内的专家共识。
结果：我们正式认识到风险等位基因和低外显率变异是与导致高渗透性疾病不同的变异类别，需要对其临床分类和报告进行特殊考虑。首先,我们提供了这些变体的首选术语。第二,我们将重点放在风险等位基因上,并详细考虑了相关研究,并提出了对这些变异进行分类的框架.最后,我们讨论了风险等位基因临床报告的注意事项.
结论：这些建议支持统一的解释，分类，并报告外显谱低端的变体。
方法：此处介绍的工作是内部和社区Likert规模调查的产物，并结合工作组内的专家共识。
结果：我们正式认识到风险等位基因和低外显率变异是与导致高渗透性疾病不同的变异类别，需要对其临床分类和报告进行特殊考虑。首先,我们提供了这些变体的首选术语。第二,我们将重点放在风险等位基因上,并详细考虑了相关研究,并提出了对这些变异进行分类的框架.最后,我们讨论了风险等位基因临床报告的注意事项.
结论：这些建议支持统一的解释，分类，并报告外显谱低端的变体。
