About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.342_346del, p.(Leu117LysfsTer14)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong
This variant is a 5-bp deletion that causes a frameshift with premature termination, p.(Leu117LysfsTer14) / p.(L117Kfs*14). RUNX1 loss of function is an established disease mechanism in the RUNX1 MM-VCEP specification, and this early truncating event is expected to result in loss of normal protein function, so PVS1 is met at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the RUNX1 MM-VCEP PM2_supporting threshold of less than or equal to 0.00005 with adequate population sampling. PM2 is met at supporting strength.
PM5Supporting
PM5 · supporting
The RUNX1 MM-VCEP specification allows PM5_supporting for nonsense and frameshift variants that are downstream of c.98 in the RUNX1 reference transcript. This variant is a frameshift at c.342_346del, which is downstream of c.98, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, satisfying the splice caveat. MM-VCEP pilot data also show precedent for a downstream RUNX1 frameshift curated with PM5_supporting, so PM5 is met at supporting strength.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PVS1 very strong (+8) + PM2 supporting (+1) + PM5 supporting (+1) + PP5 supporting (+1) = 11 points, which maps to Pathogenic.
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.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 4 met · 3 not met · 8 not assessed · 13 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.342_346del (p.(Leu117LysfsTer14), p.(L117Kfs*14)) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic, including an expert-panel Pathogenic classification from the ClinGen Myeloid Malignancy VCEP.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports very low population frequency and meets the RUNX1 PM2_supporting threshold of less than or equal to 0.00005.
This 5-bp deletion causes a frameshift with premature termination, and the RUNX1 MM-VCEP framework recognizes loss of function as an established disease mechanism; this supports PVS1 at very strong strength.
SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, below the RUNX1 splice caveat threshold of 0.20, and MM-VCEP pilot precedent shows that a downstream RUNX1 frameshift was curated with PM5_supporting together with PVS1 and PM2_supporting.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a 5-bp deletion that causes a frameshift with premature termination, p.(Leu117LysfsTer14) / p.(L117Kfs*14). RUNX1 loss of function is an established disease mechanism in the RUNX1 MM-VCEP specification, and this early truncating event is expected to result in loss of normal protein function, so PVS1 is met at very strong strength. Details ▾Hide ▴
Rule
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Evidence considered
- RUNX1 MM-VCEP includes PVS1 guidance
- RUNX1 LoF mechanism supported
- Frameshift consequence p.(Leu117LysfsTer14)
Still missing
- Direct transcript-specific confirmation from the full RUNX1 PVS1 decision tree would further document the exact branch used.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the RUNX1 MM-VCEP PM2_supporting threshold of less than or equal to 0.00005 with adequate population sampling. PM2 is met at supporting strength. Details ▾Hide ▴
Rule
PM2_Supporting: minor allele frequency less than or equal to 0.00005.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- RUNX1 PM2_supporting threshold <=0.00005
Sources
PM5 SupportingThe RUNX1 MM-VCEP specification allows PM5_supporting for nonsense and frameshift variants that are downstream of c.98 in the RUNX1 reference transcript. This variant is a frameshift at c.342_346del, which is downstream of c.98, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, satisfying the splice caveat. MM-VCEP pilot data also show precedent for a downstream RUNX1 frameshift curated with PM5_supporting, so PM5 is met at supporting strength. Details ▾Hide ▴
Rule
PM5_Supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4), provided splice caveats are satisfied.
Evidence considered
- Frameshift is downstream of c.98
- SpliceAI max delta 0.03 <= 0.20
- MM-VCEP pilot precedent: RUNX1 c.292del curated with PM5_supporting + PVS1 + PM2_supporting
Still missing
- A direct expert-panel record for this exact variant under the full RUNX1 PM5 branch was not retrieved.
Sources
Not met · 3 · evaluated, threshold not reached
PM1 Although codon 117 lies within the RUNX1 runt homology domain, the available evidence does not support applying PM1 to this frameshift deletion. In MM-VCEP pilot precedent, a nearby downstream RUNX1 frameshift was curated with PVS1, PM5_supporting, and PM2_supporting rather than PM1, so PM1 is not applied here. Details ▾Hide ▴
Rule
PM1 applies to variants affecting defined hotspot residues or other residues 89-204 within the RHD.
Evidence considered
- Variant affects codon 117 within RHD
- MM-VCEP pilot downstream frameshift precedent did not use PM1
Still missing
- The full MM-VCEP rationale for limiting PM1 in truncating variants is not directly provided in the retrieved materials.
Sources
cspec ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the RUNX1 BA1 threshold of at least 0.0015 in a continental population dataset. Details ▾Hide ▴
Rule
BA1 requires minor allele frequency at least 0.0015.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BA1 threshold >=0.0015
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the RUNX1 BS1 frequency range of 0.00015 to 0.0015. Details ▾Hide ▴
Rule
BS1 requires minor allele frequency between 0.00015 and 0.0015.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BS1 range 0.00015 to 0.0015
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
PS2_Supporting requires 1 proven de novo occurrence; PS2_Moderate requires at least 2 proven de novo occurrences in patients with FPD/AML phenotype.
Evidence considered
- No confirmed de novo evidence located
Still missing
- No parentage-confirmed de novo report was identified.
Sources
PS3 No variant-specific RUNX1 functional study was identified showing abnormal transactivation or corroborating abnormal function for this deletion, so PS3 is not applied. Details ▾Hide ▴
Rule
Variant-specific abnormal transactivation and/or secondary assay evidence required; not applicable if variant meets PVS1.
Evidence considered
- OncoKB provided gene-level literature leads only
- No exact functional assay for this variant was established
Still missing
- No variant-specific transactivation or secondary functional assay data were identified.
Sources
PS4 This variant has been reported in ClinVar, but the available evidence did not establish the number of unrelated probands meeting RUNX1 phenotypic criteria required for PS4, so PS4 is not applied. Details ▾Hide ▴
Rule
PS4_Supporting requires 1 proband, PS4_Moderate requires 2-3 probands, and PS4 requires at least 4 probands meeting RUNX1 phenotypic criteria.
Evidence considered
- ClinVar expert-panel pathogenic assertion
- Variant-associated publications listed in ClinVar
- No directly verified proband count
Still missing
- No verified count of qualifying unrelated probands was identified.
Sources
PM6 No assumed de novo occurrences without confirmed parentage were identified for this variant, so PM6 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
PM6_Supporting requires 2-3 assumed de novo occurrences; PM6 requires at least 4 assumed de novo occurrences in patients with FPD/AML phenotype.
Evidence considered
- No assumed de novo evidence located
Still missing
- No probable de novo case report was identified.
Sources
PP1 No segregation data were identified that establish co-segregation of this variant with RUNX1-related disease across the number of informative meioses required for PP1. Details ▾Hide ▴
Rule
PP1 requires 3-4 informative meioses; higher strengths require 5-6 or at least 7 informative meioses.
Evidence considered
- No qualifying segregation data located
Still missing
- No family meiosis count or pedigree-level segregation evidence was identified.
Sources
BS3 No variant-specific functional study was identified showing normal RUNX1 function for this deletion, so BS3 is not applied. Details ▾Hide ▴
Rule
BS3 requires normal transactivation with or without corroborating secondary assay evidence, depending on strength.
Evidence considered
- No exact benign functional evidence established
Still missing
- No variant-specific normal transactivation or secondary normal-function assay was identified.
Sources
BS4 No non-segregation data were identified showing this variant in unaffected relatives or absence in affected relatives across at least 2 informative meioses, so BS4 is not applied. Details ▾Hide ▴
Rule
BS4 is applicable when observed in at least 2 informative meioses.
Evidence considered
- No qualifying BS4 segregation evidence located
Still missing
- No informative non-segregation evidence was identified.
Sources
BP2 No data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 is not applied. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant.
Evidence considered
- No BP2 phase evidence located
Still missing
- No phase data or second-variant observations were identified.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is a same-amino-acid-change criterion for missense variants, with separate splice-specific guidance. This variant is a frameshift deletion, so PS1 is not applicable. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic or likely pathogenic variant regardless of nucleotide change.
Evidence considered
- Variant class is frameshift
- not missense or splice-equivalent
Sources
PM3 VCEPPM3 is not applicable in the RUNX1 MM-VCEP specification. Details ▾Hide ▴
PM4 N/APM4 in the RUNX1 MM-VCEP specification is intended for in-frame insertions or deletions and stop-loss variants. This variant is a frameshift deletion, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to in-frame indels in the RHD or stop-loss variants causing protein extension.
Evidence considered
- Variant class is frameshift
- not in-frame indel or stop-loss
Sources
PP2 VCEPPP2 is not applicable in the RUNX1 MM-VCEP specification. Details ▾Hide ▴
PP3 N/ARUNX1 PP3 is specified for missense, synonymous, or certain intronic variants using REVEL or SpliceAI thresholds. This variant is a frameshift deletion, and REVEL and BayesDel were not applicable, so PP3 is not applicable. Details ▾Hide ▴
Rule
PP3 applies to missense, synonymous, or specified intronic variants using REVEL and/or SpliceAI thresholds.
Evidence considered
- Variant class is frameshift
- SpliceAI max delta 0.03
- REVEL and BayesDel not applicable for this indel
Sources
PP4 VCEPPP4 is not applicable in the RUNX1 MM-VCEP specification because the RUNX1 phenotype is not considered sufficiently specific for this criterion. Details ▾Hide ▴
BS2 VCEPBS2 is not applicable in the RUNX1 MM-VCEP specification. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in the RUNX1 MM-VCEP specification. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in the RUNX1 MM-VCEP specification. Details ▾Hide ▴
BP4 N/ARUNX1 BP4 is specified for missense, synonymous, or intronic variants using REVEL and SpliceAI thresholds. This variant is a frameshift deletion, so BP4 is not applicable, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Details ▾Hide ▴
Rule
BP4 applies to missense, synonymous, or intronic variants under specified REVEL and SpliceAI thresholds.
Evidence considered
- Variant class is frameshift
- SpliceAI max delta 0.03 <= 0.20
Sources
BP5 VCEPBP5 is not applicable in the RUNX1 MM-VCEP specification. Details ▾Hide ▴
BP6 VCEPBP6 is not applicable in the RUNX1 MM-VCEP specification. Details ▾Hide ▴
BP7 N/ABP7 is limited to synonymous and intronic variants with low predicted splice impact or RNA evidence. This variant is a frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants under specified splicing conditions.
Evidence considered
- Variant class is frameshift
Sources
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.342_346del
- Protein (HGVS p.)
- NP_001001890.1:p.(Leu117LysfsTer14)
- GRCh38
- chr21:34880637 TCAGCC>T
- GRCh37
- chr21:36252934 TCAGCC>T
- ClinVar
- 3662819
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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ARUNX1 PP3 is specified for missense, synonymous, or certain intronic variants using REVEL or SpliceAI thresholds. This variant is a frameshift deletion, and REVEL and BayesDel were not applicable, so PP3 is not applicable. Details ▾Hide ▴
Rule
PP3 applies to missense, synonymous, or specified intronic variants using REVEL and/or SpliceAI thresholds.
Evidence considered
- Variant class is frameshift
- SpliceAI max delta 0.03
- REVEL and BayesDel not applicable for this indel
Sources
BP4 N/ARUNX1 BP4 is specified for missense, synonymous, or intronic variants using REVEL and SpliceAI thresholds. This variant is a frameshift deletion, so BP4 is not applicable, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Details ▾Hide ▴
Rule
BP4 applies to missense, synonymous, or intronic variants under specified REVEL and SpliceAI thresholds.
Evidence considered
- Variant class is frameshift
- SpliceAI max delta 0.03 <= 0.20
Sources
BP7 N/ABP7 is limited to synonymous and intronic variants with low predicted splice impact or RNA evidence. This variant is a frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants under specified splicing conditions.
Evidence considered
- Variant class is frameshift
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 15386419 ↗Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer.No paper-specific finding is recorded.
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PMID 15864279 ↗The RUNX genes: gain or loss of function in cancer.No paper-specific finding is recorded.
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PMID 17394134 ↗Fusion gene-mediated truncation of RUNX1 as a potential mechanism underlying disease progression in the 8p11 myeloproliferative syndrome.No paper-specific finding is recorded.
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PMID 18723428 ↗Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.Owen CJ et al. · 2008No paper-specific finding is recorded.
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PMID 24100448 ↗Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects.Stockley J et al. · 2013No paper-specific finding is recorded.
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PMID 33661592 ↗RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
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
Recorded maximum delta 0.030
Open source ↗
ClinVar
1 Pathogenic
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/3662819/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36252934-TCAGCC-T?dataset=…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34880637-TCAGCC-T?datas…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/RUNX1/L117Kfs*14
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.342_346del
- 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 Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 3662819)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.