Classification rationale

PVS1PM2PM5 Pathogenic

RUNX1 c.529_551dup

The RUNX1 c.529_551dup (p.(Gln185SerfsTer34)) variant has not been observed in COSMIC and has not been reported in ClinVar; OncoKB classifies this variant as Likely Oncogenic with a likely loss-of-function effect.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the RUNX1 MM-VCEP PM2_Supporting threshold of less than or equal to 0.00005.² This duplication is predicted to cause a frameshift, p.(Gln185SerfsTer34), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is consistent with applying PVS1 and PM5_Supporting under the RUNX1 MM-VCEP framework.³

PVS1 + PM2 + PM5 → Pathogenic

1 cosmic ↗clinvar ↗oncokb ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 pvs1_gene_contextpvs1_variant_assessmentspliceai ↗cspec ↗

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_001754.4 · variants mapped to exon structure

RUNX1 NM_001754.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 13 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 · 3

Strength Supporting Moderate Strong Very strong

PVS1 Very Strong review Pathogenic

This duplication causes a frameshift, NM_001754.4:c.529_551dup, predicted to produce p.(Gln185SerfsTer34) in exon 6 of 9 with premature truncation well upstream of the 3' end of RUNX1. RUNX1 loss of function is an established disease mechanism in the MM-VCEP specification, so this finding supports PVS1 at Very Strong strength.

RUNX1 MM-VCEP includes PVS1 guidance.pvs1_gene_context.json: lof_mechanism_supported = true; pvs1_gene_gate = eligible.pvs1_variant_assessment.json: variant_bucket = frameshift; suggested_default_strength = PVS1.

cspec ↗

PM2 Supporting review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed frequency is therefore 0, which is below the RUNX1 MM-VCEP PM2_Supporting threshold of less than or equal to 0.00005.

gnomAD v2.1: absent.gnomAD v4.1: absent.RUNX1 MM-VCEP PM2_Supporting threshold: frequency less than or equal to 0.00005.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PM5 Supporting review Pathogenic

RUNX1 MM-VCEP allows PM5_Supporting for nonsense or frameshift variants downstream of c.98 when splicing is not predicted to be disrupted and PM1 is not applied. This frameshift occurs at c.529_551, which is downstream of c.98, and SpliceAI shows a maximum delta score of 0.01, which is below the less than or equal to 0.20 splice caveat.

RUNX1 MM-VCEP: PM5_Supporting applies to nonsense/frameshift variants downstream of c.98 with no predicted splice effect and without PM1.SpliceAI max delta score = 0.01.RUNX1 pilot precedent includes downstream frameshift c.292del with PM5_supporting, PM2_supporting, and PVS1.

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PP1 No segregation data were identified, so co-segregation with RUNX1-related disease cannot be assessed.

PS2 No confirmed de novo occurrence with maternity and paternity established was identified, so PS2 cannot be assessed.

PM4 This variant is a frameshift duplication, not an in-frame deletion/insertion or stop-loss variant, so PM4 does not apply.

PS1 No previously established pathogenic or likely pathogenic variant producing the same amino acid change or the same splice event was identified, so PS1 was not applied.

PM6 No assumed de novo occurrence in an affected individual was identified, so PM6 cannot be assessed.

PS4 No proband data meeting RUNX1 phenotypic criteria were identified, so PS4 cannot be applied.

PM1 Although codon 185 lies within the RUNX1 runt homology domain, available evidence does not support applying PM1 to this truncating frameshift variant.

PS3 No variant-specific transactivation assay or qualifying secondary functional assay was identified, so PS3 was not applied.

Benign

BP2 No cis/trans observation with another pathogenic RUNX1 variant was identified, so BP2 cannot be assessed.

BS3 No variant-specific functional studies demonstrating normal RUNX1 function were identified, so BS3 cannot be applied.

BS4 No evidence showing non-segregation with disease in informative meioses was identified, so BS4 cannot be assessed.

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1.

N/A · 12 PP4 · PP5 · BP4 · BP3 · BP6 · BP7 · BP5 · BS2 · PP3 · PP2 · BP1 · PM3

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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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