The RUNX1 c.319_323del (p.Ala107GlnfsTer2; p.A107Qfs*2) variant has been reported in ClinVar and classified as Pathogenic by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 PM2_Supporting threshold of <=0.00005 and far below the BS1 and BA1 population thresholds.2 This 5-bp deletion causes an early frameshift with a premature stop codon, and the exact expert-panel ClinVar record states that the default RUNX1 transcript consequence p.Ala134fs is predicted to undergo nonsense-mediated decay, supporting PVS1; the same record also applied RUNX1-specific PM5_Supporting because the frameshift is downstream of c.98.3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.03), which is below the RUNX1 PP3 threshold of 0.38 and consistent with the <=0.20 splice caveat used for PM5_Supporting.4
Final classification
Pathogenic
PVS1PM2PM5PP5
RUNX1
c.319_323del
p.Ala107GlnfsTer2
This variant
The RUNX1 c.319_323del (p.Ala107GlnfsTer2; p.A107Qfs*2) variant has been reported in ClinVar and classified as Pathogenic by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.
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.
Classification rationale
PVS1PM2PM5PP5
Pathogenic
RUNX1 c.319_323del
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
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_001001890.2 · variants mapped to exon structure
RUNX1
NM_001001890.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 12 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a 5-bp frameshift deletion that causes an early premature stop codon (p.Ala107GlnfsTer2; default RUNX1 transcript consequence p.Ala134fs). RUNX1 loss of function is an established disease mechanism, and the exact ClinGen Myeloid Malignancy VCEP ClinVar record states that this frameshift is predicted to undergo nonsense-mediated decay, supporting PVS1 at very strong strength.
Frameshift with premature stop: NP_001001890.1:p.(A107Qfs*2) / NM_001754.5:p.Ala134fsRUNX1 loss of function established in the active VCEP frameworkClinVar expert-panel record for this exact genomic variant applied PVS1
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1. The exact ClinGen Myeloid Malignancy VCEP ClinVar record states that it is completely absent from population databases with at least 20x coverage for RUNX1, meeting RUNX1 PM2_Supporting.
Absent from gnomAD v2.1Absent from gnomAD v4.1ClinVar expert-panel record explicitly applied PM2_Supporting
PM5
supporting
Pathogenic
The exact ClinGen Myeloid Malignancy VCEP ClinVar record states that this frameshift is downstream of c.98 and applied PM5_Supporting under the RUNX1-specific rule for nonsense or frameshift variants in this region. SpliceAI predicts no significant splice impact (max delta score 0.03), which is below the <=0.20 splice caveat used in the RUNX1 PM5 framework.
ClinVar expert-panel record explicitly applied PM5_SupportingVariant is downstream of c.98 in the default RUNX1 transcriptSpliceAI max delta score 0.03
Assessed · not applied
· 3 not met · 9 not assessed
Pathogenic
PS1
No established alternate nucleotide change producing the same protein consequence was identified from the retrieved evidence, so PS1 was not assessed.
PS2
No confirmed de novo occurrence with both maternity and paternity established was identified for this variant, so PS2 was not assessed.
PS3
No variant-specific functional study demonstrating abnormal RUNX1 activity for this exact deletion was identified in the retrieved evidence, so PS3 was not assessed.
PS4
No exact proband count meeting RUNX1 phenotypic criteria was established from the retrieved evidence, so PS4 was not assessed.
PM1
Although this deletion affects the RUNX1 Runt homology region, the retrieved expert-panel ClinVar record for this exact variant applied PVS1, PM2_Supporting, and PM5_Supporting and did not establish PM1 for this frameshift.
PM6
No assumed de novo occurrences without full parental confirmation were identified for this variant, so PM6 was not assessed.
PP1
No segregation data with countable informative meioses were identified for this variant, so PP1 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not reach the RUNX1 BA1 threshold of >=0.0015 in any general population dataset.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not fall within the RUNX1 BS1 range of 0.00015 to 0.0015 in a qualifying general population dataset.
BS3
No well-established study showing normal function for this exact variant was identified, so BS3 was not assessed.
BS4
No informative nonsegregation data were identified for this variant, so BS4 was not assessed.
BP2
No evidence was identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 was not assessed.
N/A · 12
PM3 · PM4 · PP2 · PP3 · PP4 · BS2 · BP1 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links