Classification rationale

PM1PM2PP3 VUS

RUNX1 c.560C>T missense · exon 6

PM1 (Supporting): Ala187 sits within the RUNX1 Runt Homology Domain (residues 89-204), though not among the 13 hotspot residues. PM2 (Supporting): completely absent from gnomAD v4.1, v2.1, and gnomAD-Canada (MAF 0, below the 0.00005 threshold). PP3 (Supporting): REVEL 0.977 exceeds the 0.88 VCEP threshold for pathogenic missense prediction. Overall: VUS, from 3 supporting points (PM1 + PM2 + PP3) under the MM-VCEP RUNX1 v3.1 rule mapping 0-5 points to Uncertain Significance.

PM1 + PM2 + PP3 → VUS

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 · 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 · 3

Strength Supporting Moderate Strong Very strong

PM1 supporting Pathogenic

Met (supporting): Ala187 lies within the Runt Homology Domain (residues 89-204) but is not one of the 13 hotspot residues.

CSPEC (MM-VCEP RUNX1 v3.1) PM1 rule: PM1_strong for the 13 hotspot residues within the RHD (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204); PM1_Supporting for any other AA residue 89-204 within the RHD.Variant normalization (prefetch.json / Mutalyzer): NM_001754.4:c.560C>T -> NP_001745.2:p.(Ala187Val); residue 187 falls within RHD range 89-204 and is not among the 13 listed hotspot residues.Myeloid-Malignancy-VCEP-RUNX1-Pilot-Results.xlsx consulted per index guidance to verify code-combination usage for PM1_supporting in the RUNX1 RHD; no residue-187 entries are present in the 969-row pilot file.

cspec ↗

PM2 supporting Pathogenic

Met (supporting): the variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada (MAF 0, below the 0.00005 threshold).

RUNX1 MM-VCEP v3.1 (cspec) PM2_Supporting rule: minor allele frequency <= 0.00005 with at least 2000 alleles tested around and 20x coverage at the position; panel recommends evaluating using the GrpMax FAF when available in gnomAD v4.1.0, otherwise requiring all subpopulations to meet the threshold.gnomAD v4.1 query for chr21-34859527-G-A (GRCh38) returned 'absent' (MAF = 0); absence means the GrpMax FAF is also 0, satisfying the <= 0.00005 threshold by a large margin.gnomAD v2.1 query for 21-36231824-G-A (GRCh37) returned 'absent' (MAF = 0).

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗

PP3 supporting Pathogenic

Met (supporting): REVEL score 0.977 exceeds the 0.88 VCEP threshold for pathogenic missense prediction.

MM-VCEP RUNX1 specification v3.1 (cspec): PP3 for missense variants is met when REVEL score >= 0.88 or SpliceAI >= 0.38, including creation of cryptic novel splice sites; do not use for canonical splice site variants or for variants whose splicing effect is proven by RNA analysis.REVEL score for NM_001754.4:c.560C>T (p.Ala187Val) is 0.977 (local REVEL v1.3 lookup), which is >= the VCEP threshold of 0.88; PP3 is met via the missense in-silico path.SpliceAI max delta score is 0.001 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.001, DS_DL 0.0), below the 0.38 PP3 threshold, so no splice-impact contribution to PP3.

cspec ↗spliceai ↗

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

Pathogenic

PS1 Not met: no alternate-nucleotide change at Ala187 has been established as pathogenic, and the only ClinVar record is classified uncertain.

PS2 Not assessed: no de novo occurrence or parental testing for this variant was reported in any source.

PS3 Not assessed: no variant-specific functional study exists; OncoKB reports no reviewed functional evidence for this variant.

PS4 Not assessed: no proband meeting RUNX1-phenotypic criteria was found for this variant; the single COSMIC hit is somatic.

PM5 Not met: no pathogenic variant at residue 187 exists as a comparator, and PM1 application independently bars PM5.

PM6 Not assessed: no assumed de novo occurrences of this variant are reported in any source.

PP1 Not assessed: no pedigree, segregation, or meiosis data for this variant is available.

PP5 Not met: the only expert-panel ClinVar classification for this exact variant is Uncertain Significance, not Pathogenic.

Benign

BA1 Not met: the variant is absent from gnomAD (MAF 0), far below the 0.0015 BA1 threshold.

BS1 Not met: MAF 0 is below the 0.00015 lower bound of the BS1 band in gnomAD.

BS3 Not assessed: no assay demonstrates normal transactivation (80-115% of wild-type) for this variant.

BS4 Not assessed: no genotype-negative, phenotype-positive family members or informative meioses were reported.

BP2 Not met: no homozygous, trans, or cis observations of this variant with a pathogenic allele were reported.

BP4 Not met: REVEL 0.977 fails the <0.50 requirement, so the missense benign-prediction rule is not satisfied.

BP6 Not met: the only expert-panel ClinVar classification for this exact variant is Uncertain Significance, not Benign.

N/A · 10 PVS1 · PM3 · PM4 · PP2 · PP4 · BS2 · BP1 · BP3 · BP5 · 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.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

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). (ClinVarID = 2850045)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.977. BayesDel score = 0.539458.

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 previously been reported in somatic cancers (COSMIC; COSV55882830, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

33661592 ↗ RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies. CLINVAR

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