Classification rationale

PM2 BP4 VUS

RUNX1 c.1132C>G

The RUNX1 c.1132C>G (p.Leu378Val, p.L378V) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Uncertain Significance, including an expert-panel submission from the ClinGen Myeloid Malignancy Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2_Supporting under the RUNX1 VCEP threshold of less than or equal to 0.00005.² Computational evidence supports a benign effect: REVEL is 0.323, below the RUNX1 BP4 cutoff of less than 0.50, SpliceAI max delta is 0.00, at or below the BP4 cutoff of 0.20, and BayesDel is negative at -0.252196.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 revelspliceai ↗bayesdelcspec ↗

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 · 2 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 VCEP PM2_Supporting threshold of less than or equal to 0.00005.

gnomAD v2.1 absentgnomAD v4.1 absentRUNX1 PM2_supporting threshold

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 supporting Benign

For this missense variant, REVEL is 0.323, which is below the RUNX1 VCEP BP4 cutoff of less than 0.50, and SpliceAI max delta is 0.00, which is at or below the BP4 cutoff of 0.20. BayesDel is also negative at -0.252196, which is directionally consistent with a non-damaging interpretation.

REVEL 0.323SpliceAI max delta 0.00BayesDel -0.252196

cspec ↗spliceai ↗

Assessed · not applied · 7 not met · 8 not assessed

Pathogenic

PVS1 This variant is a missense substitution, p.(Leu378Val), and does not fall into the RUNX1 loss-of-function categories used for PVS1.

PS1 No previously established pathogenic or likely pathogenic RUNX1 variant producing the same amino acid change was identified in the available expert-panel precedent materials or ClinVar, so PS1 is not met.

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be assessed from the available evidence.

PS3 No variant-specific functional study showing altered RUNX1 function was identified, so PS3 cannot be assessed from the available evidence.

PS4 No proband-level evidence was identified showing this variant in one or more individuals meeting RUNX1 phenotypic criteria, so PS4 cannot be assessed from the available evidence.

PM1 This missense variant affects Leu378, which is outside the RUNX1 Runt homology domain residue range used for PM1 (residues 89-204) and is not one of the specified PM1_strong residues.

PM5 No different pathogenic or likely pathogenic missense change at this amino acid residue was identified in the available expert-panel precedent materials, and SpliceAI does not suggest a splice effect that would change this interpretation.

PM6 No assumed de novo occurrences without full parental confirmation were identified for this variant, so PM6 cannot be assessed from the available evidence.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.

PP3 REVEL is 0.323, which is below the RUNX1 VCEP PP3 cutoff of 0.88, and SpliceAI max delta is 0.00, which is below the PP3 splice cutoff of 0.38.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the RUNX1 BA1 threshold of at least 0.0015.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the RUNX1 BS1 frequency range of 0.00015 to 0.0015.

BS3 No well-established functional study showing normal RUNX1 function for this variant was identified, so BS3 cannot be assessed.

BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 cannot be assessed.

N/A · 11 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 = 0.00). REVEL score = 0.323. BayesDel score = -0.252196.

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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