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ALK L1196M
GeneALK
Variantmissense
Amino Acid ChangeL1196M
DNA Change (Coding Nucleotide)3586C>A
Transcript ID (GRCh37/hg19)ENST00000389048
Codon1196
Exon23
Genomic Coordinates (GRCh37/hg19)2:29443631-29443631
COSMIC ID99137
Germline/Somatic?Somatic
Pertinent Negative In
Tumor TypePrimary Site
See All Pertinent Negatives

Interpretations

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Tier 2
ALK
Variants
ALK L1196M
ALK L1196Q
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. L1196 is present in the gatekeeper position at the bottom of the ATP-binding pocket of the protein. Gatekeeper genetic alterations seem to confer TKI resistance in oncogenic tyrosine kinases. L1196M mutant confers high-level resistance to crizotinib, but has been shown to be sensitive to ceretinib.

Last updated: 2020-07-24 14:53:09 UTC
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When using PMKB, please cite: Huang et al., JAMIA 2017


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