Rare germline ETV6 variant associated with thrombocytopenia and acute leukemia
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".