Classification rationale

PM2 BP4 VUS

RUNX1 c.1036T>G

The RUNX1 NM_001001890.2:c.1036T>G (p.(Ser346Ala)) 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 threshold of <=0.00005.² Computational evidence argues against a damaging effect because REVEL is 0.262, below the RUNX1 PP3 threshold and within the BP4 range, SpliceAI shows no predicted splice impact with a max delta score of 0.00, and BayesDel is -0.17459.³

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 · 14 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 PM2_Supporting threshold of <=0.00005.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 supporting Benign

Computational evidence supports a benign interpretation because the REVEL score is 0.262, below the RUNX1 BP4 threshold of <0.50, and the SpliceAI max delta score is 0.00, within the <=0.20 threshold for no predicted splice impact. The BayesDel score of -0.17459 is also consistent with low predicted deleteriousness.

REVEL score 0.262.SpliceAI max delta score 0.00.BayesDel score -0.17459.

spliceai ↗cspec ↗

Assessed · not applied · 12 not met · 2 not assessed

Pathogenic

PS1 No evidence was identified that this variant causes the same amino acid change as a previously established pathogenic or likely pathogenic RUNX1 variant.

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

PS3 No variant-specific functional study demonstrating abnormal RUNX1 function was identified, so PS3 could not be evaluated from the available evidence.

PS4 No affected proband count or enrichment data were identified for this variant, so case-level overrepresentation has not been established.

PM1 This missense change affects Ser346, which is outside the RUNX1 Runt homology domain residues used by the RUNX1 specification for PM1, and no hotspot evidence supports this site as a critical region.

PM5 No evidence was identified that a different pathogenic or likely pathogenic missense variant has been established at this same residue, so PM5 is not supported.

PM6 No assumed de novo occurrences without full parental confirmation were identified for this variant.

PP1 No segregation data were identified for this variant, so cosegregation with RUNX1-related disease has not been established.

PP3 Available computational evidence does not support a damaging effect under the RUNX1 PP3 rule because REVEL is 0.262, below the >=0.88 threshold, and SpliceAI is 0.00, below the >=0.38 threshold.

Benign

BA1 This variant is absent from population databases and does not meet the RUNX1 BA1 threshold of >=0.0015 in a general population dataset.

BS1 This variant is absent from population databases and does not meet the RUNX1 BS1 range of 0.00015 to 0.0015.

BS3 No variant-specific functional study showing normal RUNX1 activity was identified, so BS3 could not be evaluated from the available evidence.

BS4 No lack-of-segregation data were identified for this variant, so BS4 is not supported.

BP2 No evidence was identified that this variant is observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant.

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 = 0.00). REVEL score = 0.262. BayesDel score = -0.17459.

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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