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.1 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 0.00005.2 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.3 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.4
RUNX1
Final classification
Pathogenic
RUNX1 c.342_346del · p.Leu117LysfsTer14
RUNX1
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.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PVS1 very strong (+8) + PM2 supporting (+1) + PM5 supporting (+1) + PP5 supporting (+1) = 11 points, which maps to Pathogenic.
Classification rationale
PVS1PM2PM5PP5
Pathogenic
RUNX1 c.342_346del
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessment
4
spliceai ↗cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results
Gene diagram
· NM_001001890.2 · variants mapped to exon structure
RUNX1
NM_001001890.2
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 3662819)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
15386419 ↗
Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer.
ONCOKB
17394134 ↗
Fusion gene-mediated truncation of RUNX1 as a potential mechanism underlying disease progression in the 8p11 myeloproliferative syndrome.
ONCOKB
18723428 ↗
Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.
CLINVAR
24100448 ↗
Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR