The RUNX1 c.342_346del (p.(Leu117LysfsTer14), p.(L117Kfs*14)) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic, including an expert-panel Pathogenic classification from the ClinGen Myeloid Malignancy VCEP.
clinvar ↗This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports very low population frequency and meets the RUNX1 PM2_supporting threshold of less than or equal to 0.00005.
gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗This 5-bp deletion causes a frameshift with premature termination, and the RUNX1 MM-VCEP framework recognizes loss of function as an established disease mechanism; this supports PVS1 at very strong strength.
cspec ↗SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, below the RUNX1 splice caveat threshold of 0.20, and MM-VCEP pilot precedent shows that a downstream RUNX1 frameshift was curated with PM5_supporting together with PVS1 and PM2_supporting.
spliceai ↗ cspec ↗
