Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Ambry Genetics, Aliso Viejo, CA.
Genet Med. 2022 Mar;24(3):673-680. doi: 10.1016/j.gim.2021.10.018. Epub 2021 Nov 30.
Some variants identified by multigene panel testing of DNA from blood present with low variant allele fraction (VAF), often a manifestation of clonal hematopoiesis. Research has shown that the proportion of variants with low VAF is especially high in TP53, the Li-Fraumeni syndrome gene. Based on the hypothesis that variants with low VAF are positively selected as drivers of clonal hematopoiesis, we investigated the use of VAF as a predictor of TP53 germline variant pathogenicity.
We used data from 260,681 TP53 variants identified at 2 laboratories to compare the distribution of pathogenic and benign variants at different VAF intervals.
Likelihood ratios toward pathogenicity associated with a VAF < 26% equated to the American College of Medical Genetics/Association of Molecular Pathology strong strength level and were applicable for 1 in 5 variants of unknown significance.
In conclusion, detection of variants with low VAF in blood can be considered an in vivo functional assay to aid assessment of TP53 variant pathogenicity.
通过对血液 DNA 进行多基因panel 检测发现的一些变体，其变异等位基因分数（VAF）较低，这通常是克隆性造血的表现。研究表明，在 Li-Fraumeni 综合征基因 TP53 中，低 VAF 变体的比例特别高。基于低 VAF 变体被积极选择为克隆性造血驱动因素的假设，我们研究了 VAF 作为 TP53 种系变体致病性预测因子的用途。
我们使用了 2 个实验室鉴定的 260681 个 TP53 变体的数据，比较了不同 VAF 间隔的致病性和良性变体的分布。
VAF < 26% 与致病性相关的似然比相当于美国医学遗传学学院/分子病理学协会的强强度水平，适用于 1/5 个意义不明的变体。
总之，血液中低 VAF 变体的检测可以被认为是一种体内功能测定，以帮助评估 TP53 变体的致病性。
