ABL1

Final classification

Likely Pathogenic

ABL1 c.1001C>T · p.Thr334Ile

ABL1

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

Gene

ABL1

Transcript

NM_007313.2

HGVS · transcript:coding

NM_007313.2:c.1001C>T

Consequence

N/A

GRCh38

chr9:130872896 C>T

GRCh37

chr9:133748283 C>T

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic.

Classification rationale

PS3PM1PM2PP3 Likely Pathogenic

ABL1 c.1001C>T

This variant has not been observed in population databases (absent from gnomAD v2.1, v4.1, and Canada; PM2).¹ 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).² 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).³ REVEL in silico prediction score of 0.587 supports a deleterious effect on protein function (PP3).⁴ 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.⁵ 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.

PS3 + PM1 + PM2 + PP3 → Likely Pathogenic

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 PMID:10988075 ↗PMID:11423618 ↗

3 PMID:11423618 ↗PMID:25686603 ↗

4 revel

5 generic_acmg_combination_rules

Gene diagram · NM_007313.2 · variants mapped to exon structure

ABL1 NM_007313.2

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

Error retrieving ClinVar entry.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.587. BayesDel score = 0.236673.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ABL1, a tyrosine kinase, is frequently altered by chromosomal translocations in leukemia.

OncoKB ↗

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; COSV59323790, n = 91 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & References.

Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.

PMID 10988075 ↗ · Schindler T et al. · 2000 Sep 15 CLINVAR · functional

Searched

T315IThr315Ile944C>T1001C>Tmutation

Found

Reports the crystal structure of the wild-type ABL1 catalytic domain bound to an STI-571 variant at 2.4 Å resolution. Identifies Thr315 as a residue whose side chain forms a critical hydrogen bond with STI-571. The T315I mutation is not mentioned in this paper; the study was published prior to the clinical discovery of the T315I resistance mutation.

Variant

◇ Residue / gene-level — variant not named

Applied to

→PM1 supports · met

Why

Provides structural context that residue Thr315 (Thr334) is in the ATP-binding pocket and critical for STI-571 binding; used to support PM1 domain argument, not for variant-specific functional evidence.

Thr315 is among those that form critical hydrogen bonds with STI-571.

Location Results, paragraph describing hydrogen bonding interactions with inhibitor · Context Crystallography of murine ABL1 kinase domain (aa 229-515) with STI-571 variant; spectrophotometric kinase assay for inhibition · full text

Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.

PMID 11423618 ↗ · Gorre ME et al. · 2001 Aug 3 CLINVAR · case observation

Searched

c.1001C>TT315IThr315IleC>T944

Found

T315I (Thr315Ile) identified in 6 of 9 STI-571-resistant CML patients by cDNA sequencing. Reconstitution of T315I into wild-type p210 BCR-ABL in 293T cells confirmed the mutant retained phosphotyrosine activity at all STI-571 concentrations tested, demonstrating the T315I substitution is sufficient to confer drug resistance. Structural modeling predicted the isoleucine substitution would eliminate a critical hydrogen bond with STI-571 and create a steric clash.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 supports · met

Why

Variant-specific functional data confirmed T315I confers STI-571 resistance; referenced in PS3 assessment.

A single, identical C→T nucleotide (nt) change was detected at ABL nt 944 in six of nine cases examined. ... This single nucleotide C→T change results in a threonine to isoleucine substitution at position 315 (Thr315→Ile; T315I) of c-Abl.

Location Abstract; Results, paragraphs 2-4; Fig. 4 · Context BCR-ABL reconstitution assay, 293T cells; STI-571 dose-response (0-10 µM); anti-phosphotyrosine and anti-Abl immunoblotting · full text

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.

PMID 25686603 ↗ · Pemovska T et al. · 2015 Mar 5 CLINVAR · functional

Searched

T315IThr315Ilegatekeeper

Found

BCR-ABL1(T315I) gatekeeper mutation shown to be potently inhibited by axitinib. Crystal structures of axitinib bound to ABL1(T315I) revealed an active DFG-in conformation distinct from the DFG-out conformation in wild-type ABL1. Axitinib inhibited ABL1(T315I) with Ki=100 pM versus Ki=3,800 pM for wild-type. Axitinib suppressed T315I autophosphorylation and Ba/F3 cell proliferation with ~10-fold higher potency compared to wild-type. Clinical treatment of a T315I-positive CML patient resulted in rapid reduction of T315I transcript levels.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 supports · met

Why

Extensive structural, biochemical, and cellular functional data confirm altered ABL1(T315I) kinase properties; referenced in PS3 assessment.

The BCR–ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations.

Location Abstract; Results, paragraphs 1-6; Fig. 2-4 · Context Crystallography (axitinib-ABL1 and axitinib-ABL1(T315I) co-crystals); biochemical kinase inhibition (Ki determination); Ba/F3 cell proliferation and autophosphorylation ELISA; ex vivo drug sensitivity testing of primary CML/Ph+ ALL patient cells; clinical case treatment (5 mg axitinib twice daily) · full text

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

24976289 ↗ Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years. CLINVAR

36063163 ↗ Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC). CLINVAR