Gene Variant Detail

Transcript	gDNA	cDNA	Protein	Source Database	Genome Build
NM_004304	chr2:g.29220765G>T	c.3586C>A	p.L1196M	RefSeq	GRCh38/hg38

Molecular Profiles 21
Evidence 51

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Molecular Profile	Protein Effect	Treatment Approaches
EML4-ALK ALK L1196M ALK F1174C
NPM1-ALK ALK L1122V ALK L1196M
EML4-ALK ALK L1196M ALK F1174L
ALK rearrange ALK V1180L ALK L1196M ALK G1202R
ALK rearrange ALK G1202R ALK L1196M
EML4-ALK ALK L1196M ALK L1256F
EML4-ALK ALK L1196M ALK G1202R
ALK rearrange ALK L1196M
NPM1-ALK ALK L1196M ALK D1203N		ASP3026
EML4-ALK ALK L1196M ALK I1171S
EML4-ALK ALK L1196M		Brigatinib Ceritinib Ensartinib Entrectinib Lorlatinib Repotrectinib
EML4-ALK ALK L1196M ALK L1198F
ALK L1196M	gain of function - predicted	ALK Inhibitor
ALK fusion ALK L1196M
EML4-ALK ALK L1196M ALK I1179V
EML4-ALK ALK L1196M ALK F1174V
EML4-ALK ALK G1269A ALK L1196M
NPM1-ALK ALK L1196M		Brigatinib Ceritinib
EML4-ALK ALK C1156Y ALK L1196M
NPM1-ALK ALK L1196M ALK S1206C
EML4-ALK ALK L1196M ALK L1198H

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4-ALK ALK L1196M ALK F1174C	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK F1174C was identified as a compound mutation in transformed cells expressing ALK L1196M in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
NPM1-ALK ALK L1122V ALK L1196M	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1122V ALK L1196M	Advanced Solid Tumor	resistant	ASP3026	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to ASP3026 treatment in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1122V ALK L1196M	anaplastic large cell lymphoma	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Alunbrig (brigatinib) in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1122V ALK L1196M	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Xalkori (crizotinib) treatment in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1122V ALK L1196M	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1122V and ALK L1196M were resistant to Alecensa (alectinib) treatment in culture (PMID: 25421750).	25421750
EML4-ALK ALK L1196M ALK F1174L	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK F1174L was identified as a compound mutation in transformed cells expressing ALK L1196M in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
ALK rearrange ALK V1180L ALK L1196M ALK G1202R	lung non-small cell carcinoma	predicted - resistant	Brigatinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK G1202R and ALK L1196M were identified at disease progression while on Alunbrig (brigatinib) treatment in liquid biopsy of a patient with ALK-positive non-small cell lung cancer also harboring an ALK V1180L (PMID: 29935304).	29935304
ALK rearrange ALK G1202R ALK L1196M	lung non-small cell carcinoma	resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical study, an ALK-positive non-small cell lung cancer patient harboring ALK G1202R ALK L1196M developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534).	29650534
EML4-ALK ALK L1196M ALK L1256F	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK L1256F was identified as a compound mutation in transformed cells expressing ALK L1196M in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
EML4-ALK ALK L1196M ALK G1202R	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK L1196M was identified as a compound mutation in transformed cells expressing ALK G1202R in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
ALK rearrange ALK L1196M	lung non-small cell carcinoma	resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK L1196M was identified in biopsies from a non-small cell lung cancer patient harboring an ALK rearrangement who developed resistance to Xalkori (crizotinib) (PMID: 22277784).	22277784
ALK rearrange ALK L1196M	lung non-small cell carcinoma	resistant	Crizotinib	Case Reports/Case Series	Actionable	In a retrospective analysis, four non-small cell lung cancer patients harboring an ALK rearrangement responded to Xalkori (crizotinib) therapy, but then progressed, and were found to have acquired ALK L1196M (PMID: 25724526).	25724526
NPM1-ALK ALK L1196M ALK D1203N	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N were resistant to Alunbrig (brigatinib) treatment in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M ALK D1203N	Advanced Solid Tumor	sensitive	ASP3026	Preclinical - Cell culture	Actionable	In a preclinical study, ASP3026 inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M ALK D1203N	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N were resistant to Xalkori (crizotinib) treatment in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M ALK D1203N	Advanced Solid Tumor	decreased response	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical trial, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M ALK D1203N	Advanced Solid Tumor	decreased response	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M and ALK D1203N to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750).	25421750
EML4-ALK ALK L1196M ALK I1171S	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK I1171S was identified as a compound mutation in transformed cells expressing ALK L1196M in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
EML4-ALK ALK L1196M	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M in the context of EML4-ALK were insensitive to Xalkori (crizotinib) as demonstrated by a lack of growth inhibition and Alk phosphorylation in culture (PMID: 26698910).	26698910
EML4-ALK ALK L1196M	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing ALK L1196M in the context of EML4-ALK were resistant to Xalkori (crizotinib) in culture (PMID: 22277784).	22277784
EML4-ALK ALK L1196M	lung non-small cell carcinoma	sensitive	Ceritinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Zykadia (ceritinib) inhibited cell survival and PI3K/AKT, MEK/ERK, and mTOR signaling in two human non-small cell lung carcinoma cell lines harboring the Xalkori (crizotinib) resistance mutation EML4-ALK ALK L1196M in culture and inhibited tumor growth in xenograft models of one of those cell lines (PMID: 24675041).	24675041
EML4-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Entrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M were sensitive to Entrectinib (RXDX-101), resulting in anti-proliferative activity in culture (PMID: 26939704).	26939704
EML4-ALK ALK L1196M	Advanced Solid Tumor	conflicting	Alectinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing an EML4-ALK fusion and ALK L1196M in culture and in cell line xenograft models (PMID: 21575866).	21575866
EML4-ALK ALK L1196M	Advanced Solid Tumor	conflicting	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M demonstrated decreased sensitivity to Alecensa (alectinib) compared to cells expressing EML4-ALK with wild-type ALK, in culture (PMID: 26698910).	26698910
EML4-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Brigatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Alunbrig (brigatinib) inhibited growth of transformed cells expressing ALK L196M in the context of EML4-ALK in culture and reduced tumor growth in cell line xenograft models (PMID: 27780853).	27780853
EML4-ALK ALK L1196M	Advanced Solid Tumor	sensitive	WX-0593	Preclinical - Cell culture	Actionable	In a preclinical study, WX-0593 inhibited growth of transformed cells expressing ALK L1196M in the context of EML4-ALK in culture (Cancer Res 2018;78(13 Suppl):Abstract nr 4794).	detail...
EML4-ALK ALK L1196M	lung non-small cell carcinoma	sensitive	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Alunbrig (brigatinib) inhibited growth of non-small cell lung cancer cells expressing ALK L1196M in the context of EML4-ALK in culture (PMID: 21502504).	21502504
EML4-ALK ALK L1196M	Advanced Solid Tumor	conflicting	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M were resistant to growth inhibition mediated by Lorlatinib (PF-06463922) in culture (PMID: 26698910), however, in another study, comparable cells demonstrated sensitivity in culture (PMID: 27432227).	26698910 27432227
EML4-ALK ALK L1196M	lung non-small cell carcinoma	sensitive	Lorlatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and proliferation of non-small cell lung carcinoma cells over expressing ALK L1196M in the context of EML4-ALK in culture, and resulted in tumor regression in cell line xenograft models (PMID: 26144315).	26144315
EML4-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing EML4-ALK with ALK L1196M in culture (PMID: 26698910)	26698910
EML4-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing EML4-ALK and ALK L1196M demonstrated sensitivity to treatment with Zykadia (ceritinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Ensartinib	Preclinical	Actionable	In a preclinical study, Ensartinib (X-396) inhibited growth and Alk phosphorylation in cells expressing the Xalkori (crizotinib) resistance mutation, EML4-ALK ALK L1196M (PMID: 21613408).	21613408
EML4-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Repotrectinib (TPX-0005) inhibited Alk activity and proliferation of transformed cells over expressing ALK L1196M in the context of EML4-ALK in culture (European Journal of Cancer , Volume 69, S32).	detail...
EML4-ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, introduction of an additional ALK mutation L1198F in transformed cells expressing ALK L1196M in the context of EML4-ALK reduced resistance to Xalkori (crizotinib) mediated growth inhibition in culture (PMID: 26698910).	26698910
EML4-ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M and ALK L1198F were resistant to growth inhibition mediated by Alunbrig (brigatinib) in culture (PMID: 26698910).	26698910
EML4-ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M and ALK L1198F displayed enhanced resistance to growth inhibition mediated by Lorlatinib (PF-06463922) in culture (PMID: 26698910).	26698910
EML4-ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M and ALK L1198F displayed enhanced resistance to growth inhibition mediated by Alecensa (alectinib) in culture (PMID: 26698910).	26698910
EML4-ALK ALK L1196M ALK L1198F	Advanced Solid Tumor	resistant	Ceritinib	Preclinical	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M and ALK L1198F displayed enhanced resistance to growth inhibition mediated by Zykadia (ceritinib) in culture (PMID: 26698910).	26698910
ALK L1196M	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell culture	Actionable	In a preclinical study, Repotrectinib (TPX-0005) inhibited cell proliferation in transformed cell lines over expressing ALK L1196M in culture (AACR, Cancer Res: April 2016; Volume 57, Abstract #2132).	detail...
EML4-ALK ALK L1196M ALK I1179V	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK I1179V was identified as a compound mutation in transformed cells expressing ALK L1196M in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
EML4-ALK ALK L1196M ALK F1174V	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK F1174V was identified as a compound mutation in transformed cells expressing ALK L1196M in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
EML4-ALK ALK G1269A ALK L1196M	lung non-small cell carcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical study, a patient with non-small cell lung cancer harboring EML4-ALK demonstrated a partial response when treated with Xalkori (crizotinib), however, after 6 months the patient progressed and was found to harbor two secondary resistance mutations, ALK G1269A and ALK L1196M (PMID: 23344087).	23344087
EML4-ALK ALK G1269A ALK L1196M	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK L1196M was identified as a compound mutation in transformed cells expressing ALK G1269A in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
NPM1-ALK ALK L1196M	Advanced Solid Tumor	resistant	ASP3026	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK L1196M were resistant to ASP3026 treatment in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M	Advanced Solid Tumor	decreased response	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical trial, Xalkori (crizotinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical trial, Zykadia (ceritinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M	Advanced Solid Tumor	decreased response	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical trial, Alecensa (alectinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M to a lesser degree than cells expressing NPM1-ALK in culture (PMID: 25421750).	25421750
NPM1-ALK ALK L1196M	Advanced Solid Tumor	sensitive	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Alunbrig (brigatinib) inhibited growth of transformed cells expressing NPM1-ALK with ALK L1196M in culture (PMID: 25421750).	25421750
EML4-ALK ALK C1156Y ALK L1196M	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK L1196M was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534).	29650534
EML4-ALK ALK C1156Y ALK L1196M	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with lung adenocarcinoma harboring EML4-ALK treated on a clinical trial achieved a partial response when treated with Xalkori (crizotinib), however, after 5 months, the patient progressed and was found to harbor secondary resistance mutations, ALK C1156Y and ALK L1196M (PMID: 20979473; NCT00585195).	20979473

Gene	ALK
Variant	L1196M
Impact List	missense
Protein Effect	gain of function - predicted
Gene Variant Descriptions	ALK L1196M lies within the protein kinase domain of the Alk protein (UniProt.org). L1196M is predicted to confer a gain of function to the Alk protein as demonstrated by transformation activity and modest autophosphorylation of Alk in culture (PMID: 25517749), and confers resistance to Alk inhibitors in the context of ALK rearrangements in culture (PMID: 21613408, PMID: 25421750).
Associated Drug Resistance	Y