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
Final classification
Pathogenic
PVS1PM2PM5PP5
RUNX1
c.342_346del
p.Leu117LysfsTer14
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_001001890.2 · variants mapped to exon structure
RUNX1
NM_001001890.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 11 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
This variant is a 5-bp deletion that causes a frameshift with premature termination, p.(Leu117LysfsTer14) / p.(L117Kfs*14). RUNX1 loss of function is an established disease mechanism in the RUNX1 MM-VCEP specification, and this early truncating event is expected to result in loss of normal protein function, so PVS1 is met at very strong strength.
RUNX1 MM-VCEP includes PVS1 guidanceRUNX1 LoF mechanism supportedFrameshift consequence p.(Leu117LysfsTer14)
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the RUNX1 MM-VCEP PM2_supporting threshold of less than or equal to 0.00005 with adequate population sampling. PM2 is met at supporting strength.
Absent from gnomAD v2.1Absent from gnomAD v4.1RUNX1 PM2_supporting threshold <=0.00005
PM5
supporting
review
Pathogenic
The RUNX1 MM-VCEP specification allows PM5_supporting for nonsense and frameshift variants that are downstream of c.98 in the RUNX1 reference transcript. This variant is a frameshift at c.342_346del, which is downstream of c.98, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, satisfying the splice caveat. MM-VCEP pilot data also show precedent for a downstream RUNX1 frameshift curated with PM5_supporting, so PM5 is met at supporting strength.
Frameshift is downstream of c.98SpliceAI max delta 0.03 <= 0.20MM-VCEP pilot precedent: RUNX1 c.292del curated with PM5_supporting + PVS1 + PM2_supporting
Assessed · not applied
· 3 not met · 8 not assessed
Pathogenic
PS2
No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence.
PS3
No variant-specific RUNX1 functional study was identified showing abnormal transactivation or corroborating abnormal function for this deletion, so PS3 is not applied.
PS4
This variant has been reported in ClinVar, but the available evidence did not establish the number of unrelated probands meeting RUNX1 phenotypic criteria required for PS4, so PS4 is not applied.
PM1
Although codon 117 lies within the RUNX1 runt homology domain, the available evidence does not support applying PM1 to this frameshift deletion.
PM6
No assumed de novo occurrences without confirmed parentage were identified for this variant, so PM6 cannot be applied from the available evidence.
PP1
No segregation data were identified that establish co-segregation of this variant with RUNX1-related disease across the number of informative meioses required for PP1.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the RUNX1 BA1 threshold of at least 0.0015 in a continental population dataset.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the RUNX1 BS1 frequency range of 0.00015 to 0.0015.
BS3
No variant-specific functional study was identified showing normal RUNX1 function for this deletion, so BS3 is not applied.
BS4
No non-segregation data were identified showing this variant in unaffected relatives or absence in affected relatives across at least 2 informative meioses, so BS4 is not applied.
BP2
No data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 is not applied.
N/A · 13
PS1 · PM3 · PM4 · PP2 · PP3 · PP4 · BS2 · BP1 · BP3 · BP4 · BP5 · BP6 · BP7
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