The RUNX1 c.1332_1334delinsG (p.Leu445GlyfsTer127) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification by the ClinGen Myeloid Malignancy VCEP.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the RUNX1 PM2_Supporting threshold of 0.00005.2 This is a RUNX1 frameshift variant in a gene with an established loss-of-function disease mechanism, supporting use of the RUNX1 PVS1 framework, although the distal position suggests a downgraded rather than full very-strong PVS1 strength.3 SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which supports the RUNX1 PM5_Supporting rule for downstream nonsense or frameshift variants and does not support PP3 or BP4 application for this frameshift event.4
Final classification
Likely Pathogenic
PVS1PM2PM5PP5
RUNX1
c.1332_1334delinsG
p.Leu445GlyfsTer127
This variant
The RUNX1 c.1332_1334delinsG (p.Leu445GlyfsTer127) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification by the ClinGen Myeloid Malignancy VCEP.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PVS1 strong (+4) + PM2 supporting (+1) + PM5 supporting (+1) + PP5 supporting (+1) = 7 points, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2PM5PP5
Likely Pathogenic
RUNX1 c.1332_1334delinsG
PVS1 + PM2 + PM5 + PP5
→
Likely Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessment
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 · 9 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
strong
review
Pathogenic
This variant is a RUNX1 frameshift variant in a gene with an established loss-of-function disease mechanism. Because the frameshift occurs near the 3' end and is predicted to alter the terminal portion of the protein rather than undergo classic nonsense-mediated decay, a downgraded PVS1 strength is appropriate under the RUNX1-specific framework; PVS1_Strong is supported pending manual confirmation of distal-region handling.
RUNX1 VCEP includes PVS1 as an applicable criterionRUNX1 loss of function is an established disease mechanismVariant is a frameshift near the transcript terminus
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the RUNX1 PM2_Supporting threshold of 0.00005.
Absent from gnomAD v2.1Absent from gnomAD v4.1RUNX1 PM2_Supporting threshold is <=0.00005
PM5
supporting
review
Pathogenic
Under the RUNX1 specification, PM5_Supporting can be applied to nonsense and frameshift variants downstream of c.98. This variant is a downstream frameshift, SpliceAI predicts no significant splice effect with a max delta score of 0.00, and PM1 does not apply, so PM5_Supporting is met.
Frameshift is downstream of c.98SpliceAI max delta score = 0.00PM1 not applied
Assessed · not applied
· 2 not met · 7 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.
PS4
This variant is reported in ClinVar, including an expert-panel classification, but the available evidence does not provide a verified count of affected probands meeting RUNX1 phenotypic criteria.
PM6
No assumed de novo occurrences without full parentage confirmation were identified for this variant, so PM6 cannot be applied from the available evidence.
PP1
No segregation data were identified for this variant, so PP1 cannot be applied.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the RUNX1 BA1 threshold of at least 0.0015.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the RUNX1 BS1 frequency range of 0.00015 to 0.0015.
BS3
No directly reviewed functional studies showing normal RUNX1 function for this variant were identified, so BS3 cannot be applied.
BS4
No non-segregation data were identified for this variant, so BS4 cannot be applied.
BP2
No evidence was identified that this variant was observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant, so BP2 cannot be applied.
N/A · 15
PS1 · PS3 · PM1 · 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 Uncertain significance (1 clinical laboratory) and as Likely Pathogenic by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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