ASXL1 encodes a chromatin-binding protein of the Polycomb group that helps regulate gene expression by recruiting repressive complexes (such as PRC2) to chromatin and modifying histone marks. Germline mutations in ASXL1 cause Bohring-Opitz syndrome, a developmental disorder with distinctive craniofacial abnormalities. Somatic loss-of-function mutations in ASXL1 are common in blood cancers, including myelodysplastic syndromes, chronic myelomonocytic leukemia, myelofibrosis, and acute myeloid leukemia, where the gene acts as a tumor suppressor. Loss of ASXL1 function disrupts normal repression of target genes, contributing to leukemogenesis.

ASXL1 truncating mutations are established drivers in myeloid malignancies, and germline loss-of-function variants cause Bohring-Opitz syndrome, giving this last-exon truncation a plausible disease mechanism. The VUS classification reflects that this specific allele lacks the functional, familial, or population evidence needed to confirm or refute pathogenicity.