NM_015338.5:c.2822delC

ASXL1 · NP_056153.2:p.(Pro941LeufsTer4) · NM_015338.5

GRCh37: chr20:31023335 GC>G · GRCh38: chr20:32435532 GC>G

Gene: ASXL1 Transcript: NM_015338.5

Final call

Likely Pathogenic

PVS1_Strong PM2_Supporting

Variant details

Gene

ASXL1

Transcript

NM_015338.5

Protein

NP_056153.2:p.(Pro941LeufsTer4)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The ASXL1 c.2822del (p.(Pro941LeufsTer4)) variant has been observed in somatic cancers and is absent from ClinVar.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is not applicable because this is a frameshift deletion, not an alternate nucleotide change producing the same amino acid substitution as a known pathogenic variant.	pvs1_variant_assessment
PS2	Not assessed	No confirmed de novo data were identified for this variant, so PS2 cannot be assessed.
PS3	Not assessed	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.	oncokb PMID:19388938 PMID:21455215 PMID:22897849 PMID:24216483 PMID:26095772
PS4	Not met	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.	oncokb clinvar
PM1	Not met	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.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	Not assessed	No phase data or recessive case data were identified, so PM3 cannot be assessed.
PM4	N/A	PM4 is not applicable because this is a frameshift loss-of-function variant that is evaluated under PVS1 rather than an in-frame length change or stop-loss event.	pvs1_variant_assessment
PM5	N/A	PM5 is not applicable because this variant is not a novel missense change at an amino acid residue with a previously established pathogenic missense variant.	pvs1_variant_assessment
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified, so PM6 cannot be assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.
PP2	N/A	PP2 is not applicable because this is not a missense variant.	pvs1_variant_assessment
PP3	N/A	PP3 is not applied because this frameshift deletion is already assessed through loss-of-function evidence, and SpliceAI predicts no significant additional splice effect with a maximum delta score of 0.02.	spliceai pvs1_variant_assessment
PP4	Not assessed	No phenotype information was provided that is sufficiently specific for a single genetic etiology, so PP4 cannot be assessed.
PP5	Not met	This variant is absent from ClinVar, so there is no external pathogenic assertion available to support PP5.	clinvar
BA1	Not met	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%. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	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%. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults in a manner inconsistent with disease, so BS2 cannot be assessed.
BS3	Not assessed	No well-established functional study demonstrating a normal or benign effect for this specific variant was identified, so BS3 cannot be assessed.	oncokb PMID:19388938 PMID:21455215 PMID:22897849 PMID:24216483 PMID:26095772
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed.
BP1	N/A	BP1 is not applicable because this is not a missense variant.	pvs1_variant_assessment
BP2	Not assessed	No phase data with another variant were identified, so BP2 cannot be assessed.
BP3	Not assessed	No evidence was identified showing that this deletion lies in a repetitive region without known function, so BP3 cannot be assessed.
BP4	Not met	Available computational evidence does not support a benign interpretation. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but this does not offset the predicted truncating effect of the frameshift variant.	spliceai pvs1_variant_assessment
BP5	Not assessed	No alternate molecular explanation for the phenotype was identified, so BP5 cannot be assessed.
BP6	Not met	This variant is absent from ClinVar, so there is no external benign assertion available to support BP6.	clinvar
BP7	N/A	BP7 is not applicable because this variant is neither synonymous nor intronic.	pvs1_variant_assessment

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