Variant classification summary

NM_005157.6:c.944C>T

ABL1 · NP_005148.2:p.(Thr315Ile) · NM_005157.6

GRCh37: chr9:133748283 C>T · GRCh38: chr9:130872896 C>T

Gene: ABL1 Transcript: NM_005157.6

Final call

VUS

PS3 moderate PM2 supporting

Variant details

Gene

ABL1

Transcript

NM_005157.6

Protein

NP_005148.2:p.(Thr315Ile)

gnomAD AF

ClinVar

association

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate: orthogonal biochemical, cellular, and in vivo assays showed activating and damaging effects of ABL1 T315I.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate pathogenic criterion plus one supporting pathogenic criterion does not satisfy any Likely Pathogenic or Pathogenic rule, while no benign rule is satisfied; therefore the call is VUS.

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	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no documented pathogenic alternate-nucleotide change producing p.Thr315Ile was available for the required same-amino-acid comparison.	clinvar
PS2	Not assessed	Not assessed: no documented affected proband, absent family history, or confirmed maternity and paternity establishes a de novo occurrence.	clinvar
PS3	Met	Met at moderate strength: ABL1 T315I increased kinase activity, drove IL-3-independent BaF3 proliferation, and caused leukemia in mice across orthogonal functional assays.	PMID:18794843
PS4	Not met	Not met: no variant-specific affected-versus-control counts, odds ratio, or confidence interval demonstrate the PS4 requirement of OR/RR >5.0 with CI excluding 1.0.	PMID:24976289
PM1	Not assessed	Not assessed: T315 is an active-site gatekeeper, but domain-wide absence of benign variation required by PM1 was not established.	PMID:18794843 hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, below the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no parent/offspring phase data or documented pathogenic variant in trans are available for NM_005157.6:c.944C>T.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense substitution at ABL1 residue 315 was documented for comparison with p.Thr315Ile.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: germline origin is recorded, but no affected-patient de novo observation without confirmed parental testing is documented.	clinvar
PP1	Not assessed	Not assessed: no affected relatives, genotypes, or informative meioses are documented to evaluate co-segregation.
PP2	Not assessed	Not assessed: the evidence provides neither a benign-missense rate nor proof that missense is ABL1's common disease mechanism.
PP3	Not met	Not met: missense REVEL score 0.587 is below the PP3 supporting threshold of 0.644 and remains in the gray zone.	revel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history is available to establish a highly specific single-etiology disease presentation.	clinvar
PP5	Not met	Not met: the exact-variant ClinVar record has zero expert-panel submissions, so ordinary Pathogenic or Likely pathogenic assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its filtering allele frequency is not >=0.05 for BA1.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its filtering allele frequency is not >=0.01 and is not greater than expected.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult individual carrying the variant is documented, so the BS2 observation requirement cannot be evaluated.
BS3	Not met	Not met: direct assays showed increased ABL1 kinase activity, IL-3-independent cell proliferation, and leukemia in mice rather than a benign functional effect.	PMID:18794843
BS4	Not assessed	Not assessed: no affected relatives with documented variant status are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: available ABL1 evidence shows both missense gain-of-function and loss-of-function disease, not primarily truncating disease.
BP2	Not assessed	Not assessed: no documented pathogenic variant in trans or cis, and no phase or inheritance evidence, is available for NM_005157.6:c.944C>T.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.587 exceeds the BP4 supporting threshold of 0.29 and is indeterminate for a benign computational effect.	revel
BP5	Not assessed	Not assessed: COSMIC reports one somatic occurrence, but no documented case shows an alternate molecular basis for the disease.	cosmic
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present to trigger BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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