Classification rationale

PM2 VUS

RUNX1 c.556C>G

The RUNX1 c.556C>G (p.Gln186Glu) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen Myeloid Malignancy Variant Curation Expert Panel classified the canonical transcript change NM_001754.5:c.637C>G (p.Gln213Glu) as uncertain significance.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting RUNX1 PM2_Supporting because the observed allele frequency is 0 and therefore below the VCEP threshold of 0.00005.² Computational evidence does not meet the RUNX1 thresholds for either PP3 or BP4: SpliceAI predicts no significant splice effect with a max delta score of 0.01, REVEL is 0.59, and BayesDel is 0.0862396.³

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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 · 1 applied · 15 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the RUNX1 VCEP PM2_Supporting threshold of 0.00005.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.RUNX1 VCEP PM2_Supporting threshold is MAF <= 0.00005.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Assessed · not applied · 5 not met · 10 not assessed

Pathogenic

PS1 No previously established pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available ClinVar or RUNX1 VCEP materials, so PS1 was not applied.

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant.

PS3 No variant-specific functional study showing abnormal RUNX1 function was identified in the available curated sources, so PS3 was not applied.

PS4 No case series or proband count was identified showing enrichment of this variant in individuals meeting RUNX1-associated phenotype criteria, so PS4 was not applied.

PM1 Under the RUNX1 VCEP default transcript, ClinVar maps this variant to NM_001754.5:c.637C>G (p.Gln213Glu).

PM5 SpliceAI is low enough that a splice effect would not block PM5 consideration, but no previously established pathogenic or likely pathogenic different missense change at this residue was identified in the available ClinVar or RUNX1 VCEP materials, so PM5 was not applied.

PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified for this variant, so PP1 was not applied.

PP3 For RUNX1 missense variants, PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not reach 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 fall within the RUNX1 BS1 frequency range of 0.00015 to 0.0015.

BS3 No variant-specific functional study showing normal RUNX1 function was identified, so BS3 was not applied.

BS4 No non-segregation data were identified for this variant, so BS4 was not applied.

BP2 No evidence was identified showing this variant in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant, so BP2 was not applied.

BP4 For RUNX1 missense variants, BP4 requires REVEL < 0.50 and SpliceAI <= 0.20.

N/A · 12 PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.59. BayesDel score = 0.0862396.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic ma

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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