Gene Variant Detail

Transcript	gDNA	cDNA	Protein	Source Database	Genome Build
NM_004304	chr2:g.29220744C>T	c.3607G>A	p.D1203N	RefSeq	GRCh38/hg38

Molecular Profiles 10
Evidence 32

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Molecular Profile	Protein Effect	Treatment Approaches
EML4-ALK ALK D1203N ALK E1210K		Lorlatinib
EML4-ALK ALK D1203N		Alectinib Brigatinib Ceritinib Lorlatinib
ALK rearrange ALK I1171N ALK D1203N
EML4-ALK ALK D1203N ALK F1174C
ALK D1203N	unknown
EML4-ALK ALK C1156Y ALK D1203N
ALK rearrange ALK D1203N
NPM1-ALK ALK L1196M ALK D1203N		ASP3026
ALK rearrange ALK E1210K ALK D1203N ALK G1269A
NPM1-ALK ALK C1156F ALK D1203N

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4-ALK ALK D1203N ALK E1210K	Advanced Solid Tumor	sensitive	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated sensitivity to treatment with Lorlatinib (PF-06463922) in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK E1210K	Advanced Solid Tumor	decreased response	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated a decreased response to treatment with Zykadia (ceritinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK E1210K	Advanced Solid Tumor	decreased response	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated a decreased response to treatment with Alunbrig (brigatinib) when compared to cells expressing EML4-ALK in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK E1210K	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K did not response to treatment with Alecensa (alectinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK E1210K	Advanced Solid Tumor	decreased response	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated a decreased response to treatment with Xalkori (crizotinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N	Advanced Solid Tumor	resistant	TAE684	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells overexpressing ALK D1203N in the context of EML4-ALK were resistant to TAE684 in culture (PMID: 21948233).	21948233
EML4-ALK ALK D1203N	Advanced Solid Tumor	decreased response	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated a decreased response to treatment with Xalkori (crizotinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N	Advanced Solid Tumor	sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Zykadia (ceritinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N	Advanced Solid Tumor	sensitive	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Alunbrig (brigatinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N	Advanced Solid Tumor	sensitive	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Alecensa (alectinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N	Advanced Solid Tumor	sensitive	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Lorlatinib (PF-06463922) in culture (PMID: 27432227).	27432227
ALK rearrange ALK I1171N ALK D1203N	non-small cell lung carcinoma	resistant	Lorlatinib	Clinical Study	Actionable	In a clinical study, an ALK-positive non-small cell lung cancer patient harboring ALK I1171N and D1203N in cis developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534).	29650534
EML4-ALK ALK D1203N ALK F1174C	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated resistance to treatment with Zykadia (ceritinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK F1174C	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated resistance to treatment with Xalkori (crizotinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK F1174C	Advanced Solid Tumor	decreased response	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated a decreased response to treatment with Lorlatinib (PF-06463922) in culture compared to cells expressing wild-type EML4-ALK (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK F1174C	Advanced Solid Tumor	decreased response	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated a decreased response to treatment with Alunbrig (brigatinib) when compared to cells expressing EML4-ALK in culture (PMID: 27432227).	27432227
EML4-ALK ALK D1203N ALK F1174C	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C did not response to treatment with Alecensa (alectinib) in culture (PMID: 27432227).	27432227
EML4-ALK ALK C1156Y ALK D1203N	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, ALK D1203N 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
ALK rearrange ALK D1203N	non-small cell lung carcinoma	predicted - resistant	Brigatinib	Clinical Study	Actionable	In a clinical case study, ALK D1203N was identified at disease progression while on Alunbrig (brigatinib) treatment in a patient with ALK-positive non-small cell lung cancer (PMID: 29935304).	29935304
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
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	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	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
ALK rearrange ALK E1210K ALK D1203N ALK G1269A	non-small cell lung carcinoma	resistant	Lorlatinib	Clinical Study	Actionable	In a clinical study, ALK G1269A was identified as an acquired mutation in an ALK-positive non-small cell lung cancer patient harboring ALK E1210K and D1203N who developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534).	29650534
NPM1-ALK ALK C1156F ALK D1203N	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and D1203N were resistant to Xalkori (crizotinib) in culture (PMID: 25749034).	25749034
NPM1-ALK ALK C1156F ALK D1203N	Advanced Solid Tumor	resistant	Brigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and D1203N were resistant to Alunbrig (brigatinib) in culture (PMID: 25749034).	25749034
NPM1-ALK ALK C1156F ALK D1203N	anaplastic large cell lymphoma	resistant	ASP3026	Preclinical - Cell culture	Actionable	In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK with ALK C1156F and D1203N were resistant to ASP3026 mediated growth inhibition in culture (PMID: 25749034).	25749034
NPM1-ALK ALK C1156F ALK D1203N	Advanced Solid Tumor	resistant	ASP3026	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and ALK D1203N were resistant to ASP3026 in culture (PMID: 25749034).	25749034
NPM1-ALK ALK C1156F ALK D1203N	Advanced Solid Tumor	resistant	Alectinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and D1203N were resistant to Alecensa (alectinib) in culture (PMID: 25749034).	25749034
NPM1-ALK ALK C1156F ALK D1203N	Advanced Solid Tumor	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with C1156F and D1203N were resistant to Zykadia (ceritinib) in culture (PMID: 25749034).	25749034
NPM1-ALK ALK C1156F ALK D1203N	Advanced Solid Tumor	resistant	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NPM1-ALK with ALK C1156F and ALK D1203N were resistant to Lorlatinib (PF-06463922) in culture (PMID: 25749034).	25749034

Gene	ALK
Variant	D1203N
Impact List	missense
Protein Effect	unknown
Gene Variant Descriptions	ALK D1203N lies within the protein kinase domain of the Alk protein (UniProt.org). D1203N has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK and ALK L1196M (PMID: 25421750), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2018).
Associated Drug Resistance	Y