Curating the Clinical Genome 2024 ePoster Gallery-Refinement of RUNX1 Variant Curation Through Bayesian Modeling

Refinement of RUNX1 Variant Curation Through Bayesian Modeling

Pdf Summary

This study focuses on germline RUNX1 variants in patients with RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM). Despite efforts using ACMG-AMP guidelines, over 50% of variants remain classified as variants of uncertain significance (VUS) due to data insufficiency. The study explores identifying variants for reclassification through hypothetical evidence to prioritize them for functional assessments. Variant curation for the RUNX1 gene utilized static and literature-based codes, excluding segregations and proband data. Bayesian modeling and the EVE tool were used to categorize variants as likely benign or pathogenic. Existing functional evidence was applied to ClinVar-deposited variants. Only a small number of variants were reclassified out of the VUS range, emphasizing the importance of patient data. Most variants in ClinVar are without patient information, and without additional data, variants will likely remain VUS. Functional testing is crucial, particularly in the RHD region. Future directions include refining the framework, incorporating gene-wide functional testing, and prioritizing variants with high posterior probabilities for further testing. This study sheds light on the challenges in variant classification and the importance of patient data in reclassifying variants.

Keywords

germline RUNX1 variants

RUNX1 familial platelet disorder with associated myeloid malignancies

ACMG-AMP guidelines

variants of uncertain significance

variant curation

Bayesian modeling

EVE tool

ClinVar-deposited variants

functional testing

reclassifying variants