Rare germline ETV6 variant associated with thrombocytopenia and acute leukemia

Germline mutations in ETV6 have been associated with thrombocytopenia and predisposition to hematological malignancies. Here, we report a pedigree with a multiple family member with an ETV6 c.1127T > A (p.Leu376Gln) variant, initially classified as a variant of uncertain significance (VUS), found to be segregating with thrombocytopenia and hematological/solid tumor malignancies. The proband, a 63-year-old male with chronic thrombocytopenia and a family history of hematological malignancies, presented with pancytopenia and was diagnosed as myelodysplastic syndrome (MDS). Next generation sequencing (NGS) from the bone marrow revealed the ETV6 c.1127T > A (p.Leu376Gln) variant with a variant allele frequency (VAF) of 46%. Germline testing on skin fibroblasts confirmed the presence of the same ETV6 variant in the proband and two of his siblings: one of them was diagnosed with acute lymphoblastic leukemia (ALL) during childhood and therapy-related MDS during adulthood, and another sibling with chronic isolated thrombocytopenia. The ETV6 c.1127T > A (p.Leu376Gln) variant potentially affects the ETS DNA-binding domain, leading to impaired DNA binding with a preserved dimerization capability, resulting in a dominant negative effect by cytoplasmic sequestration. This ETV6 variant has not been reported in a large population database, hence it has been designated as a VUS. Segregation of this variant with thrombocytopenia and hematological/solid tumor malignancies in the pedigree, alongside supporting evidence from other reported ETV6 variants, suggests its pathogenicity. This report highlights the pathogenicity of ETV6 c.1127T > A (p.Leu376Gln) variant and supports its reclassification from VUS to likely pathogenic, adding to the vast evidence of ETV6-associated thrombocytopenia and leukemia predisposition.