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RUNX1
Final classification
VUS
RUNX1 c.560C>T · p.Ala187Val
RUNX1 ·missense

PM1 (Supporting): Ala187 sits within the RUNX1 Runt Homology Domain (residues 89-204), though not among the 13 hotspot residues.

Gene
RUNX1
Transcript
NM_001754.4
HGVS · transcript:coding
NM_001754.4:c.560C>T
Consequence
missense
exon 6
GRCh38
chr21:34859527 G>A
GRCh37
chr21:36231824 G>A
Basis Uncertain Significance: 3 points (PM1, PM2, PP3, all supporting) under the MM-VCEP RUNX1 v3.1 rule mapping 0-5 points to VUS. ▾
Uncertain Significance: 3 points (PM1, PM2, PP3, all supporting) under the MM-VCEP RUNX1 v3.1 rule mapping 0-5 points to VUS.
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
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
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
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 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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 screenshot
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 ↗
SpliceAI screenshot
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 / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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