Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity
- Author(s)
- Fortuno, C; McGoldrick, K; Pesaran, T; Dolinsky, J; Hoang, L; Weitzel, JN; Beshay, V; San Leong, H; James, PA; Spurdle, AB;
- Details
- Publication Year 2022-03,Volume 24,Issue #3,Page 673-680
- Journal Title
- Genetics in Medicine
- Publication Type
- Research article
- Abstract
- PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
- Keywords
- *Clonal Hematopoiesis; *Genetic Predisposition to Disease; Germ-Line Mutation/genetics; Humans; Tumor Suppressor Protein p53/genetics; Acmg; Clonal hematopoiesis; Li-Fraumeni syndrome; Tp53; Variant allele fraction; Variant classification
- Department(s)
- Pathology; Familial Cancer Centre
- PubMed ID
- 34906512
- Publisher's Version
- https://doi.org/10.1016/j.gim.2021.10.018
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-10-25 06:46:33
Last Modified: 2024-10-25 06:48:14