NM_005157.6(ABL1):c.944C>T (p.Thr315Ile) AND Chronic myelogenous leukemia, BCR-ABL1 positive

Germline classification:: Likely pathogenic; association (3 submissions)
Last evaluated:: Sep 13, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000432136.4

Allele description [Variation Report for NM_005157.6(ABL1):c.944C>T (p.Thr315Ile)]

NM_005157.6(ABL1):c.944C>T (p.Thr315Ile)

Gene:

ABL1:ABL proto-oncogene 1, non-receptor tyrosine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.12

Genomic location:

Preferred name:

NM_005157.6(ABL1):c.944C>T (p.Thr315Ile)

HGVS:

NC_000009.12:g.130872896C>T
NG_012034.1:g.164016C>T
NM_005157.6:c.944C>TMANE SELECT
NM_007313.3:c.1001C>T
NP_005148.2:p.Thr315Ile
NP_009297.2:p.Thr334Ile
LRG_769t1:c.944C>T
LRG_769t2:c.1001C>T
LRG_769:g.164016C>T
LRG_769p1:p.Thr315Ile
LRG_769p2:p.Thr334Ile
NC_000009.11:g.133748283C>T
NM_005157.5:c.944C>T

Protein change:

T315I; THR315ILE

Links:

OMIM: 189980.0001; dbSNP: rs121913459

NCBI 1000 Genomes Browser:

rs121913459

Molecular consequence:

NM_005157.6:c.944C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007313.3:c.1001C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Chronic myelogenous leukemia, BCR-ABL1 positive (CML)
Synonyms:: Chronic myeloid leukemia; Chronic granulocytic leukemia; Chronic myelogenous leukemia
Identifiers:: MONDO: MONDO:0011996; MeSH: D015464; MedGen: C0279543; Orphanet: 521; OMIM: 608232; Human Phenotype Ontology: HP:0005506

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000505087	Database of Curated Mutations (DoCM)	no assertion criteria provided	Likely pathogenic (Mar 10, 2016)	somatic	literature only	PubMed (23) [See all records that cite these PMIDs] 12399961, 12130516, 14745431, 11423618, 21872826, 20537386, 23355941, 20963643, 21762985, 21562040, 11853795, 23540562, 20367437, 23676790, 20512393, 12623848, 21895409, 15194504, 24236021, 25157968, 11964322, 22306673, 22870928 Citation Link,
SCV002318661	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004034968	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (Horak et al. (Genet Med. 2022))	association (Sep 13, 2023)	somatic	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000505087

Database of Curated Mutations (DoCM)

no assertion criteria provided

Likely pathogenic
(Mar 10, 2016)

somatic

literature only

PubMed (23)
[See all records that cite these PMIDs]

Citation Link,

SCV002318661

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 22, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004034968

KCCC/NGS Laboratory, Kuwait Cancer Control Center

criteria provided, single submitter

(Horak et al. (Genet Med. 2022))

association
(Sep 13, 2023)

somatic

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	somatic	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.

Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R.

Leukemia. 2002 Nov;16(11):2190-6.

PubMed [citation]

PMID:: 12399961

Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment.

Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Laï JL, Philippe N, Facon T, Fenaux P, Preudhomme C.

Blood. 2002 Aug 1;100(3):1014-8.

PubMed [citation]

PMID:: 12130516

See all PubMed Citations (25)

Details of each submission

From Database of Curated Mutations (DoCM), SCV000505087.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (23)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	somatic	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002318661.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with ABL1 related disorder (ClinVar ID: VCV000012624). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (ClinVar ID: VCV000376118). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004034968.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ABL1, a tyrosine kinase, is frequently altered by chromosomal translocations in leukemia. The BCR-ABL1 fusion is known to be oncogenic. The ABL1 T315I is a known resistance mutation. Diagnostic Summary: The presence of a BCR-ABL1 fusion is consistent with the diagnosis of chronic myeloid leukemia. Therapeutic Summary: The presence of the BCR-ABL1 fusion in myeloproliferative neoplasms is diagnostic of chronic myelogenous leukemia (CML). The NCCN considers the ABL1 T315I mutation as "contraindicated" for the therapies imatinib, dasatinib, nilotinib, and bosutinib in patients with BCR-ABL1 positive (+) CML. The multikinase inhibitor ponatinib and the BCR-ABL1 inhibitor asciminib are FDA approved for adult patients with ABL1 T315I+ BCRABL1 fusion+ CML.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	somatic	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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