NM_007313.2:c.1001C>T

ABL1 · NP_009297.2:p.(Thr334Ile) · NM_007313.2

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

Gene: ABL1 Transcript: NM_007313.2

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

ABL1

Transcript

NM_007313.2

Protein

NP_009297.2:p.(Thr334Ile)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant has not been observed in population databases (absent from gnomAD v2.1, v4.1, and Canada; PM2).

The c.1001C>T (p.Thr334Ile) substitution alters the gatekeeper residue in the ATP-binding pocket of the ABL1 kinase domain, a critical functional domain where pathogenic missense variants cluster without benign variation (PM1).

Well-established in vitro functional studies demonstrate that the T315I substitution disrupts imatinib/STI-571 binding to the ABL1 kinase. Reconstitution experiments showed the mutant retained kinase activity at all STI-571 concentrations (PMID:11423618), and crystallographic studies confirmed a distinct active conformation with differential inhibitor binding (PMID:25686603) (PS3).

REVEL in silico prediction score of 0.587 supports a deleterious effect on protein function (PP3).

Three moderate criteria (PM1, PM2, PS3) and one supporting criterion (PP3) are met. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), 3 moderate criteria alone meet the threshold for Likely Pathogenic.

Note: The T315I substitution is established as a somatic drug-resistance mutation in BCR-ABL1-driven leukemias. Germline disease association for this specific variant has not been established; ABL1 germline disorders (CHDSKM, HADS) are associated with different residue substitutions. This assessment applies the generic ACMG/AMP framework to the variant irrespective of disease context.

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	N/A	NM_007313.2:c.1001C>T is a missense variant (p.Thr334Ile). Per ClinGen SVI PVS1 recommendations (PMC6185798), it does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 framework does not apply.	pvs1_generic_framework
PS1	N/A	PS1 applies when a novel nucleotide change produces the same amino acid change as a previously established pathogenic variant. NM_007313.2:c.1001C>T is itself the established pathogenic T315I gatekeeper variant, not a novel nucleotide substitution yielding the same missense change.
PS2	Not assessed	No de novo germline observation of NM_007313.2:c.1001C>T was identified in the reviewed literature. The variant is predominantly reported in somatic/acquired contexts (leukemia drug resistance).
PS3	Met	Well-established in vitro functional studies demonstrate that the T315I (p.Thr334Ile) substitution in the ABL1 kinase domain disrupts imatinib/STI-571 binding. Reconstitution experiments in 293T cells (PMID:11423618) showed the T315I mutant retained kinase activity at all STI-571 concentrations tested, confirming drug resistance. Crystallographic and biochemical studies (PMID:25686603) demonstrated axitinib binds the T315I mutant in an active DFG-in conformation distinct from wild-type, with Ki=100 pM for the mutant versus 3,800 pM for wild-type. Multiple independent functional assays from two laboratories support a deleterious functional effect.	PMID:11423618 PMID:25686603
PS4	Not assessed	The variant has been observed in 6 of 9 relapsed CML patients (PMID:11423618) and is reported 91 times in COSMIC (COSV59323790), but all observations are in somatic/acquired leukemia contexts. No germline case-control data comparing affected individuals to population controls is available for this variant.	PMID:11423618
PS5	Not assessed	ClinVar lists the variant as Likely pathogenic from a single clinical testing submitter (3billion, criteria provided) and Pathogenic from OMIM (no assertion criteria). These do not meet the PS5 threshold requiring a reputable source recently reporting the variant as pathogenic with evidence not independently available.	clinvar
PM1	Met	The c.1001C>T (p.Thr334Ile) variant alters the gatekeeper residue (Thr315 in canonical numbering) located in the ATP-binding pocket of the ABL1 kinase domain. This is a critical functional domain of the tyrosine kinase where pathogenic missense variants cluster without benign variation. The ClinVar 3billion submission also applied PM1.	PMID:11423618 PMID:10988075 clinvar
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency 0.0%). Per non-VCEP generic ACMG thresholds, PM2 applies when a variant is absent or present at <0.1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies when a novel missense variant occurs at an amino acid residue where a different pathogenic missense change has been previously established. NM_007313.2:c.1001C>T (p.Thr334Ile/T315I) is itself the well-established pathogenic change at this residue. Per pm5_candidates.json, no eligible same-residue comparator variants satisfying classic PM5 semantics were identified.
PM6	Not assessed	No assumed or confirmed de novo occurrence of NM_007313.2:c.1001C>T was identified in the reviewed literature in a germline context. PM6 requires assumed de novo with unconfirmed maternity/paternity.
PP1	Not met	No cosegregation data for NM_007313.2:c.1001C>T in affected family members was identified. PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not assessed	PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. GnomAD missense constraint (Z-score) data was not retrieved for ABL1, and no HCI prior score is available. Cannot formally assess PP2 without gene-level missense constraint metrics.
PP3	Met	REVEL score of 0.587 exceeds the 0.5 threshold for deleterious prediction. BayesDel score of 0.237 provides additional in silico support. SpliceAI predicts no splicing impact (max delta 0.00), consistent with a missense variant whose pathogenic mechanism is at the protein level.	revel bayesdel spliceai
PP4	Not met	PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient phenotype information was provided for this variant in a germline disease context.
PP5	Not assessed	ClinVar variation 12624 is classified as Likely pathogenic by a single submitter with criteria provided (3billion) and as Pathogenic by OMIM (no assertion criteria). The pediatric CML guideline (PMID:24976289) lists T315I among known resistance mutations but provides no independent variant-level evidence. This does not meet the PP5 threshold requiring a reputable source to have recently reported the variant as pathogenic with evidence not independently available to the laboratory.	clinvar PMID:24976289
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and Canada. Allele frequency 0.0% is well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all gnomAD population databases (allele frequency 0.0%). Does not meet the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in a healthy adult individual for a disorder with full penetrance expected at an early age. BS2 requires observation in trans for recessive disorders or in a healthy adult for dominant fully penetrant early-onset disorders.
BS3	Not met	Well-established in vitro functional studies (PMID:11423618, PMID:25686603) demonstrate a damaging effect of the T315I substitution on ABL1 kinase drug binding, not a benign effect. BS3 requires functional studies showing no damaging effect.	PMID:11423618 PMID:25686603
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease in affected family members. BS4 requires such evidence to be met.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. ABL1-associated germline disorders (CHDSKM, HADS) are caused by both missense (gain-of-function: p.Tyr245Cys, etc.) and loss-of-function variants. BP1 is not met.
BP2	Not met	No observation of NM_007313.2:c.1001C>T in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP4	Not met	REVEL score of 0.587 predicts a deleterious effect (>0.5 threshold). BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product, which is contradicted by the REVEL prediction. SpliceAI max delta of 0.00 alone is insufficient to override the REVEL prediction.	revel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such observation was identified.
BP6	Not met	ClinVar classifies this variant as Likely pathogenic (criteria provided, single submitter) and Pathogenic (OMIM, no assertion criteria). BP6 requires a reputable source to report the variant as benign. ClinVar reports are in the opposite direction.	clinvar
BP7	N/A	NM_007313.2:c.1001C>T is a missense variant (p.Thr334Ile). BP7 applies only to synonymous variants with no predicted splice impact. SpliceAI max delta is 0.00, but the variant is inherently missense and BP7 is reserved for synonymous variants.

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