About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.556C>G, p.(Gln186Glu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen RUNX1 VCEP v3.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen RUNX1 VCEP v3.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
No criteria match.
Met · 1
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
RUNX1 VCEP PM2_Supporting: minor allele frequency <= 0.00005.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- RUNX1 VCEP PM2_Supporting threshold is MAF <= 0.00005.
Still missing
- The reviewed summaries did not explicitly report grpMax FAF or site coverage metrics.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 Under the RUNX1 VCEP default transcript, ClinVar maps this variant to NM_001754.5:c.637C>G (p.Gln213Glu). The RUNX1 PM1 region is limited to residues 89-204 in the Runt homology domain, and p.Gln213 is outside that range; Cancer Hotspots also did not identify a hotspot signal at this residue. Details ▾Hide ▴
Rule
RUNX1 VCEP PM1 applies only to defined residues within the Runt homology domain on the default transcript.
Evidence considered
- ClinVar title: NM_001754.5(RUNX1):c.637C>G (p.Gln213Glu).
- RUNX1 VCEP PM1 applies to residues 89-204
- with stronger weighting for 13 specified residues.
- Cancer Hotspots did not identify a hotspot row for Q186/Q213.
Still missing
- No residue-level structural review was available beyond the defined VCEP rule and hotspot screen.
Sources
PP3 For RUNX1 missense variants, PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38. This variant has REVEL 0.59, BayesDel 0.0862396, and SpliceAI max delta 0.01, so the available computational evidence does not meet the RUNX1 PP3 threshold. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3 for missense variants requires REVEL >= 0.88 or SpliceAI >= 0.38.
Evidence considered
- REVEL score 0.59.
- BayesDel score 0.0862396.
- SpliceAI max delta score 0.01.
- RUNX1 VCEP PP3 threshold: REVEL >= 0.88 or SpliceAI >= 0.38.
Still missing
- No additional validated computational framework beyond the VCEP rule was identified.
Sources
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. Details ▾Hide ▴
Rule
RUNX1 VCEP BA1 requires minor allele frequency >= 0.0015.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- RUNX1 VCEP BA1 threshold is >= 0.0015.
Sources
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. Details ▾Hide ▴
Rule
RUNX1 VCEP BS1 requires minor allele frequency between 0.00015 and 0.0015.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- RUNX1 VCEP BS1 range is 0.00015 to 0.0015.
Sources
BP4 For RUNX1 missense variants, BP4 requires REVEL < 0.50 and SpliceAI <= 0.20. SpliceAI is low at 0.01, but REVEL is 0.59, so the VCEP BP4 rule is not met. BayesDel is available at 0.0862396, but the RUNX1 VCEP BP4 rule is based on REVEL and SpliceAI. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4 for missense variants requires REVEL < 0.50 and SpliceAI <= 0.20.
Evidence considered
- REVEL score 0.59.
- BayesDel score 0.0862396.
- SpliceAI max delta score 0.01.
- RUNX1 VCEP BP4 threshold: REVEL < 0.50 and SpliceAI <= 0.20.
Still missing
- No additional benign computational framework beyond the VCEP rule was identified.
Sources
Not assessed · 10 · no assessment recorded
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. Details ▾Hide ▴
Rule
RUNX1 VCEP PS1 requires the same amino acid change as a previously established pathogenic or likely pathogenic variant.
Evidence considered
- ClinVar contains this variant as p.Gln213Glu on the VCEP default transcript.
- The local RUNX1 VCEP pilot file did not identify this exact amino acid substitution as a prior pathogenic or likely pathogenic precedent.
Still missing
- A complete external search for all alternate nucleotide changes causing the same amino acid substitution was not available in the reviewed sources.
Sources
clinvar ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Rule
RUNX1 VCEP PS2 requires confirmed de novo occurrence in a patient with the relevant phenotype.
Evidence considered
- Available ClinVar summary does not provide confirmed de novo evidence for this variant.
Still missing
- No parental testing data were available.
- No phenotyped de novo case report for this exact variant was identified.
Sources
PS3 No variant-specific functional study showing abnormal RUNX1 function was identified in the available curated sources, so PS3 was not applied. Details ▾Hide ▴
Rule
RUNX1 VCEP PS3 requires qualifying abnormal functional assay evidence.
Evidence considered
- Available curated sources did not provide variant-specific reviewed functional evidence.
- RUNX1 VCEP requires transactivation and/or secondary functional assay evidence for PS3.
Still missing
- No transactivation assay results were identified for this exact variant.
- No secondary functional assay results were identified for this exact variant.
Sources
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. Details ▾Hide ▴
Rule
RUNX1 VCEP PS4 requires at least 1 qualifying proband, with strength based on total count.
Evidence considered
- ClinVar reports an expert panel classification of uncertain significance but does not provide a qualifying proband count in the reviewed summary.
- RUNX1 VCEP requires phenotype-based proband counts for PS4.
Still missing
- No exact proband count was available for this variant.
- No case-control or odds ratio evidence was identified.
Sources
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. Details ▾Hide ▴
Rule
RUNX1 VCEP PM5 requires a different pathogenic or likely pathogenic missense change at the same residue and no predicted splice effect.
Evidence considered
- ClinVar maps this variant to p.Gln213Glu on the default transcript.
- SpliceAI max delta score is 0.01
- which is <= 0.20.
- No pathogenic alternate missense at this codon was identified in the reviewed ClinVar/VCEP materials.
Still missing
- A complete residue-specific search across all external databases was not available.
- No confirmed pathogenic alternate missense substitution at this codon was documented in the reviewed sources.
Sources
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Rule
RUNX1 VCEP PM6 requires 2-3 assumed de novo occurrences for Supporting or >=4 for Moderate.
Evidence considered
- Available ClinVar summary does not provide PM6-type de novo information.
- RUNX1 VCEP uses PM6 only for assumed de novo occurrences meeting phenotype criteria.
Still missing
- No case report with absent family history and incomplete parental confirmation was available.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
RUNX1 VCEP PP1 requires segregation in 3-4 meioses for Supporting, 5-6 for Moderate, or >=7 for Strong.
Evidence considered
- Available sources did not provide co-segregation evidence for this variant.
- RUNX1 VCEP PP1 requires at least 3 informative meioses for Supporting strength.
Still missing
- No family-level meiosis count was available.
- No pedigree data were identified.
Sources
BS3 No variant-specific functional study showing normal RUNX1 function was identified, so BS3 was not applied. Details ▾Hide ▴
Rule
RUNX1 VCEP BS3 requires normal functional assay evidence.
Evidence considered
- Available curated sources did not provide variant-specific reviewed functional evidence showing normal function.
- RUNX1 VCEP BS3 requires normal transactivation with or without a qualifying secondary assay depending on strength.
Still missing
- No transactivation assay results were identified for this variant.
- No secondary assay showing normal function was identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
RUNX1 VCEP BS4 requires non-segregation in >=2 informative meioses.
Evidence considered
- Available sources did not provide family-based non-segregation evidence.
- RUNX1 VCEP BS4 requires observation in at least 2 informative non-segregating meioses.
Still missing
- No informative meioses showing lack of segregation were available.
- No unaffected older carriers or affected non-carriers were identified.
Sources
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. Details ▾Hide ▴
Rule
RUNX1 VCEP BP2 requires qualifying cis or trans observations with a pathogenic variant.
Evidence considered
- Available sources did not provide phase information for this variant.
- RUNX1 VCEP allows BP2 for qualifying cis/trans observations.
Still missing
- No phase data were available.
- No second pathogenic variant in the same individual was identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant with no predicted splice disruption, so it does not fit the RUNX1 PVS1 loss-of-function framework for null or splice-disrupting variants. Details ▾Hide ▴
Rule
RUNX1 VCEP PVS1 applies to qualifying loss-of-function or splice variants; this missense change does not meet that variant type requirement.
Evidence considered
- RUNX1 VCEP includes PVS1 for appropriate loss-of-function variants.
- The variant is a missense change p.(Gln186Glu).
- SpliceAI max delta score is 0.01.
- Generic PVS1 scaffold does not place this variant in a null-variant bucket.
Still missing
- No RNA data were identified for this exact variant.
- Variant-specific transcript effect beyond in silico splice prediction was not available.
Sources
PM3 N/APM3 is not used in the RUNX1 VCEP framework for this disorder context. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks PM3 as not applicable.
Sources
PM4 N/AThis is not an in-frame insertion/deletion or stop-loss variant, so PM4 is not applicable. Details ▾Hide ▴
Rule
RUNX1 VCEP PM4 applies to in-frame indels or stop-loss variants, not missense substitutions.
Evidence considered
- The variant is a missense substitution.
- RUNX1 VCEP PM4 is defined for in-frame indels and stop-loss variants.
Sources
PP2 N/APP2 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks PP2 as not applicable.
Sources
PP4 N/APP4 is not applicable in the RUNX1 VCEP framework because the associated phenotype is not sufficiently specific for a single genetic etiology. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks PP4 as not applicable.
Sources
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks PP5 as not applicable.
Sources
BS2 N/ABS2 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks BS2 as not applicable.
Sources
BP1 N/ABP1 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks BP1 as not applicable.
Sources
BP3 N/ABP3 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks BP3 as not applicable.
Sources
BP5 N/ABP5 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks BP5 as not applicable.
Sources
BP6 N/ABP6 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP marks BP6 as not applicable.
Sources
BP7 N/AThis is a missense variant, not a synonymous or intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7 applies to synonymous or intronic variants, not missense substitutions.
Evidence considered
- The variant is a missense substitution.
- RUNX1 VCEP BP7 is defined for synonymous or intronic variants with low splice impact
- or RNA-supported splicing assessment.
Sources
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.556C>G
- Protein (HGVS p.)
- NP_001001890.1:p.(Gln186Glu)
- GRCh38
- chr21:34834578 G>C
- GRCh37
- chr21:36206875 G>C
Gene diagram
Every interpreted variant in RUNX1, mapped onto the exon structure of NM_001001890.2. Select a row to find it on the plot.
RUNX1NM_001001890.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in RUNX1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For RUNX1 missense variants, PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38. This variant has REVEL 0.59, BayesDel 0.0862396, and SpliceAI max delta 0.01, so the available computational evidence does not meet the RUNX1 PP3 threshold. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3 for missense variants requires REVEL >= 0.88 or SpliceAI >= 0.38.
Evidence considered
- REVEL score 0.59.
- BayesDel score 0.0862396.
- SpliceAI max delta score 0.01.
- RUNX1 VCEP PP3 threshold: REVEL >= 0.88 or SpliceAI >= 0.38.
Still missing
- No additional validated computational framework beyond the VCEP rule was identified.
Sources
BP4 For RUNX1 missense variants, BP4 requires REVEL < 0.50 and SpliceAI <= 0.20. SpliceAI is low at 0.01, but REVEL is 0.59, so the VCEP BP4 rule is not met. BayesDel is available at 0.0862396, but the RUNX1 VCEP BP4 rule is based on REVEL and SpliceAI. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4 for missense variants requires REVEL < 0.50 and SpliceAI <= 0.20.
Evidence considered
- REVEL score 0.59.
- BayesDel score 0.0862396.
- SpliceAI max delta score 0.01.
- RUNX1 VCEP BP4 threshold: REVEL < 0.50 and SpliceAI <= 0.20.
Still missing
- No additional benign computational framework beyond the VCEP rule was identified.
Sources
BP7 N/AThis is a missense variant, not a synonymous or intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7 applies to synonymous or intronic variants, not missense substitutions.
Evidence considered
- The variant is a missense substitution.
- RUNX1 VCEP BP7 is defined for synonymous or intronic variants with low splice impact
- or RNA-supported splicing assessment.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.59. BayesDel score = 0.0862396.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637580
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3791512/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36206875-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34834578-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.5…
- OncoKB ↗www.oncokb.org/gene/RUNX1/Q186E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.556C%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.59. BayesDel score = 0.0862396.
Functional
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.