The ASXL1 c.2822del (p.(Pro941LeufsTer4)) variant has been observed in somatic cancers and is absent from ClinVar.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the 0.1% PM2 threshold and supports rarity in the general population.2 Published studies and OncoKB support damaging loss-of-function biology for ASXL1 truncating variants, but available data do not provide a validated germline functional assay for this specific variant.3 This single-base deletion causes a frameshift predicted to truncate the protein after four altered amino acids, removing 598 of 1542 residues (38.8%), and SpliceAI predicts no significant additional splice effect with a maximum delta score of 0.02.4
Final classification
Likely Pathogenic
PVS1PM2
ASXL1
c.2822del
p.Pro941LeufsTer4
This variant
The ASXL1 c.2822del (p.(Pro941LeufsTer4)) variant has been observed in somatic cancers and is absent from ClinVar.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback.
Classification rationale
PVS1PM2
Likely Pathogenic
ASXL1 c.2822del
PVS1 + PM2
→
Likely Pathogenic
4
pvs1_variant_assessmentspliceai ↗
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_015338.5 · variants mapped to exon structure
ASXL1
NM_015338.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
strong
review
Pathogenic
This variant is a frameshift change predicted to produce p.(Pro941LeufsTer4), truncating the protein after four altered amino acids. ASXL1 loss of function is supported as a disease mechanism, so generic PVS1 assessment is appropriate; however, full very-strong weighting is not assigned from the available evidence because transcript-specific NMD and distal-region considerations were not fully resolved.
Frameshift variant NM_015338.5:c.2822del with protein consequence NP_056153.2:p.(Pro941LeufsTer4).Gene-level review supports ASXL1 loss of function as an established disease mechanism.Generic ClinGen SVI PVS1 framework applies to frameshift variants once LoF is established for the gene.
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the non-VCEP PM2 threshold of 0.1%. This supports rarity in the general population.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
Assessed · not applied
· 7 not met · 12 not assessed
Pathogenic
PS2
No confirmed de novo data were identified for this variant, so PS2 cannot be assessed.
PS3
Available studies and OncoKB support damaging biology for ASXL1 truncating variants in myeloid disease, but no well-established functional assay directly testing this specific variant in a validated germline disease framework was identified.
PS4
This variant has been observed in somatic cancers, but no evidence was identified showing enrichment in affected germline cases compared with controls, so PS4 is not met.
PM1
This variant does not have evidence for location in a well-established mutational hotspot or a critical functional domain without benign variation, so PM1 is not met.
PM3
No phase data or recessive case data were identified, so PM3 cannot be assessed.
PM6
No assumed de novo occurrence without confirmed parentage was identified, so PM6 cannot be assessed.
PP1
No segregation data were identified for this variant, so PP1 cannot be assessed.
PP4
No phenotype information was provided that is sufficiently specific for a single genetic etiology, so PP4 cannot be assessed.
PP5
This variant is absent from ClinVar, so there is no external pathogenic assertion available to support PP5.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the benign BA1 threshold of 1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the benign BS1 threshold of 0.3%.
BS2
No evidence was identified showing this variant in healthy adults in a manner inconsistent with disease, so BS2 cannot be assessed.
BS3
No well-established functional study demonstrating a normal or benign effect for this specific variant was identified, so BS3 cannot be assessed.
BS4
No non-segregation data were identified for this variant, so BS4 cannot be assessed.
BP2
No phase data with another variant were identified, so BP2 cannot be assessed.
BP3
No evidence was identified showing that this deletion lies in a repetitive region without known function, so BP3 cannot be assessed.
BP4
Available computational evidence does not support a benign interpretation.
BP5
No alternate molecular explanation for the phenotype was identified, so BP5 cannot be assessed.
BP6
This variant is absent from ClinVar, so there is no external benign assertion available to support BP6.
N/A · 7
PS1 · PM4 · PM5 · PP2 · PP3 · BP1 · 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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
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; COSV60115810, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links