The importance of genetic variant cleaners: From patient to wet lab and back to clinical practice

Laureano J. Kamiya and colleagues have identified two novel missense variants (Gly168Arg and Gly168Glu) in the RUNX1 gene. These variants, identified in two unrelated families with familial platelet disorder with a predisposition to acute myeloid leukaemia (FPD/AML) phenotype, were initially classified as variants of uncertain significance (VUS). However, functional studies of RUNX1 target genes enabled their reclassification as likely pathogenic. The findings highlight Gly168 as a new mutation hotspot in RUNX1, providing important insights for genetic counselling and leukaemia monitoring. The study emphasizes the necessity for continuous updates to diagnostic guidelines and data sharing among laboratories to improve the classification and interpretation of genetic variants. Commentary on: Kamiya et al. Two novel families with RUNX1 variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML diagnosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19776.