LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-18
Case ID: NM_001001890.2_c.342_346del_20260518_045033
Framework: ACMG/AMP 2015
Variant classification summary

NM_001001890.2:c.342_346del

RUNX1  · NP_001001890.1:p.(Leu117LysfsTer14)  · NM_001001890.2
GRCh37: chr21:36252934 TCAGCC>T  ·  GRCh38: chr21:34880637 TCAGCC>T
Gene: RUNX1 Transcript: NM_001001890.2
Final call
Pathogenic
PVS1 very strong PM2 supporting PM5 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RUNX1
Transcript
NM_001001890.2
Protein
NP_001001890.1:p.(Leu117LysfsTer14)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
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.
3
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.
4
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.
Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 11, which maps to Pathogenic under the specified Tavtigian-style ranges.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Met 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.
cspec pvs1_gene_context pvs1_variant_assessment
PS1 N/A PS1 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.
cspec
PS2 Not assessed No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence.
cspec PMID:33661592
PS3 Not assessed No variant-specific RUNX1 functional study was identified showing abnormal transactivation or corroborating abnormal function for this deletion, so PS3 is not applied.
cspec oncokb PMID:15386419 PMID:15864279 PMID:17394134
PS4 Not assessed 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.
cspec clinvar PMID:18723428 PMID:24100448 PMID:33661592
PM1 Not met 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.
cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM2 Met 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.
cspec gnomad_v2 gnomad_v4
PM3 N/A PM3 is not applicable in the RUNX1 MM-VCEP specification.
cspec
PM4 N/A PM4 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.
cspec
PM5 Met 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.
cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results pm5_candidates
PM6 Not assessed No assumed de novo occurrences without confirmed parentage were identified for this variant, so PM6 cannot be applied from the available evidence.
cspec PMID:33661592
PP1 Not assessed 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.
cspec PMID:18723428
PP2 N/A PP2 is not applicable in the RUNX1 MM-VCEP specification.
cspec
PP3 N/A RUNX1 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.
cspec spliceai
PP4 N/A PP4 is not applicable in the RUNX1 MM-VCEP specification because the RUNX1 phenotype is not considered sufficiently specific for this criterion.
cspec
PP5 Met Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Pathogenic.
cspec clinvar
BA1 Not met 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.
cspec gnomad_v2 gnomad_v4
BS1 Not met 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.
cspec gnomad_v2 gnomad_v4
BS2 N/A BS2 is not applicable in the RUNX1 MM-VCEP specification.
cspec
BS3 Not assessed No variant-specific functional study was identified showing normal RUNX1 function for this deletion, so BS3 is not applied.
cspec oncokb PMID:15386419 PMID:15864279 PMID:17394134
BS4 Not assessed 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.
cspec PMID:18723428
BP1 N/A BP1 is not applicable in the RUNX1 MM-VCEP specification.
cspec
BP2 Not assessed 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.
cspec
BP3 N/A BP3 is not applicable in the RUNX1 MM-VCEP specification.
cspec
BP4 N/A RUNX1 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.
cspec spliceai
BP5 N/A BP5 is not applicable in the RUNX1 MM-VCEP specification.
cspec
BP6 N/A BP6 is not applicable in the RUNX1 MM-VCEP specification.
cspec
BP7 N/A BP7 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.
cspec spliceai
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