ALK G1269A

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Molecular profile	Therapy	Type	Level	Direction · significance	Rating (1–5)	Status	Evidence	Source
Anaplastic Large Cell Lymphoma1
ALK G1269A AND NPM1::ALK Fusion	Crizotinib	Predictive	D	Supports Resistance	3	submitted	EID12654 In an in vitro study, a FL5.12 cell line expressing NPM1-ALK (a known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated resistance to crizotinib treatment (IC50: 871.75… (full text at CIViC) PMID 27009859 · Amin et al., 2016 · Open in CIViC	civic
Lung Adenocarcinoma1
EML4::ALK Fusion AND ALK G1269A	Crizotinib	Predictive	C	Supports Resistance	2	accepted	EID4620 In a lung adenocarcinoma cancer patient with an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, ALK G1269A was reported to be refractory to cr… (full text at CIViC)

Molecular profile

Therapy

Type

Level

Direction · significance

Rating (1–5)

Status

Evidence

Source

Anaplastic Large Cell Lymphoma1

ALK G1269A AND NPM1::ALK Fusion

Crizotinib

Predictive

Supports Resistance

submitted

EID12654

In an in vitro study, a FL5.12 cell line expressing NPM1-ALK (a known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated resistance to crizotinib treatment (IC50: 871.75… (full text at CIViC)

PMID 27009859 · Amin et al., 2016 · Open in CIViC

civic

Lung Adenocarcinoma1

EML4::ALK Fusion AND ALK G1269A

Crizotinib

Predictive

Supports Resistance

accepted

EID4620

In a lung adenocarcinoma cancer patient with an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, ALK G1269A was reported to be refractory to cr… (full text at CIViC)

Variation	Clinical significance	Review status	Stars	Conditions	Origin	Submitters	Last evaluated	Source
376132	Uncertain significance	criteria provided, multiple submitters, no conflicts	2	Neuroblastoma, susceptibility to, 3; Hereditary cancer-predisposing syndrome	germline	2	Nov 18, 2025	clinvar

Variation

Clinical significance

Review status

Stars

Conditions

Origin

Submitters

Last evaluated

Source

376132

Uncertain significance

criteria provided, multiple submitters, no conflicts

Neuroblastoma, susceptibility to, 3; Hereditary cancer-predisposing syndrome

germline

Nov 18, 2025

clinvar

Lung Non-Small Cell Carcinoma8
ALK G1269A AND EML4::ALK e6::e19 AND ALK Amplification	Crizotinib	Predictive	C	Supports Resistance	3	submitted	EID8887 This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One ALK+ patient had a novel fusion between… (full text at CIViC) PMID 22235099 · Doebele et al., 2012 · Open in CIViC	civic
ALK G1269A AND v::ALK Fusion	Ceritinib	Predictive	D	Supports Sensitivity Response	3	accepted	EID1342 The NSCLC cell line MGH021-4, harboring SQSTM1-ALK G1269A, was 6 times more sensitive to ceritinib (80nM GI50) than crizotinib (500 nM) in proliferation assays and caused notable reductions in phospho… (full text at CIViC) PMID 24675041 · Friboulet et al., 2014 · Open in CIViC	civic
ALK G1269A AND v::ALK Fusion	Crizotinib	Predictive	C	Supports Resistance	2	submitted	EID4617 In a non-small cell lung cancer patient with acquired crizotinib resistance, the tumor had an ALK gene rearrangement and an ALK G1269A co-mutation. The ALK G1269A tumor was reported to be refractory t… (full text at CIViC) PMID 23729361 · Gainor et al., 2013 · Open in CIViC	civic
ALK G1269A AND v::ALK Fusion	Crizotinib	Predictive	C	Supports Resistance	2	submitted	EID4618 In a non-small cell lung cancer patient with a bone metastatic tumor harboring an ALK gene rearrangement and an ALK G1269A co-mutation, ALK G1269A was reported to be refractory to 12-month crizotinib … (full text at CIViC) PMID 23434628 · Huang et al., 2013 · Open in CIViC	civic
ALK G1269A AND v::ALK Fusion	Ensartinib	Predictive	B	Supports Sensitivity Response	3	submitted	EID8861 In this multicentre phase II study of ALK-positive NSCLC patients that progressed on crizotinib, the safety and efficacy of 225mg daily ensartinib was assessed. Objective responses were seen in 76 (52… (full text at CIViC) PMID 31628085 · Yang et al., 2020 · Open in CIViC	civic
EML4::ALK Fusion AND ALK G1269A	Crizotinib	Predictive	C	Supports Resistance	4	accepted	EID764 This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One ALK+ patient harbored the common E6;A20… (full text at CIViC) PMID 22235099 · Doebele et al., 2012 · Open in CIViC	civic
EML4::ALK Fusion AND ALK G1269A	Crizotinib	Predictive	C	Supports Resistance	3	accepted	EID765 2 out of 7 patients with an acquired resistance to crizotinib had a G1269A mutation. One of these patients also harbored a L1196M mutation. In vitro follow-up showed reduced crizotinib-induced ALK dep… (full text at CIViC) PMID 23344087 · Kim et al., 2013 · Open in CIViC	civic
EML4::ALK Fusion AND ALK G1269A	Crizotinib	Predictive	C	Supports Resistance	2	submitted	EID4619 In a non-small cell lung cancer patient with acquired crizotinib resistance, the tumor had an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation. … (full text at CIViC) PMID 24675041 · Friboulet et al., 2014 · Open in CIViC	civic

Lung Non-Small Cell Carcinoma8

ALK G1269A AND EML4::ALK e6::e19 AND ALK Amplification

Crizotinib

Predictive

Supports Resistance

submitted

EID8887

This study analyzed patients with non small cell lung cancer (NSCLC) who were positive for EML4-ALK fusions (ALK+) and progressed on crizotinib monotherapy. One ALK+ patient had a novel fusion between… (full text at CIViC)

PMID 22235099 · Doebele et al., 2012 · Open in CIViC

civic

ALK G1269A AND v::ALK Fusion

Ceritinib

Predictive

Supports Sensitivity Response

accepted

EID1342

The NSCLC cell line MGH021-4, harboring SQSTM1-ALK G1269A, was 6 times more sensitive to ceritinib (80nM GI50) than crizotinib (500 nM) in proliferation assays and caused notable reductions in phospho… (full text at CIViC)

PMID 24675041 · Friboulet et al., 2014 · Open in CIViC

civic

ALK G1269A AND v::ALK Fusion

Crizotinib

Predictive

Supports Resistance

submitted

EID4617

In a non-small cell lung cancer patient with acquired crizotinib resistance, the tumor had an ALK gene rearrangement and an ALK G1269A co-mutation. The ALK G1269A tumor was reported to be refractory t… (full text at CIViC)

PMID 23729361 · Gainor et al., 2013 · Open in CIViC

civic

ALK G1269A AND v::ALK Fusion

Crizotinib

Predictive

Supports Resistance

submitted

EID4618

In a non-small cell lung cancer patient with a bone metastatic tumor harboring an ALK gene rearrangement and an ALK G1269A co-mutation, ALK G1269A was reported to be refractory to 12-month crizotinib … (full text at CIViC)

PMID 23434628 · Huang et al., 2013 · Open in CIViC

civic

ALK G1269A AND v::ALK Fusion

Ensartinib

Predictive

Supports Sensitivity Response

submitted

EID8861

In this multicentre phase II study of ALK-positive NSCLC patients that progressed on crizotinib, the safety and efficacy of 225mg daily ensartinib was assessed. Objective responses were seen in 76 (52… (full text at CIViC)

PMID 31628085 · Yang et al., 2020 · Open in CIViC

civic

EML4::ALK Fusion AND ALK G1269A

Crizotinib

Predictive

Supports Resistance

accepted

EID764

PMID 22235099 · Doebele et al., 2012 · Open in CIViC

civic

EML4::ALK Fusion AND ALK G1269A

Crizotinib

Predictive

Supports Resistance

accepted

EID765

2 out of 7 patients with an acquired resistance to crizotinib had a G1269A mutation. One of these patients also harbored a L1196M mutation. In vitro follow-up showed reduced crizotinib-induced ALK dep… (full text at CIViC)

PMID 23344087 · Kim et al., 2013 · Open in CIViC

civic

EML4::ALK Fusion AND ALK G1269A

Crizotinib

Predictive

Supports Resistance

submitted

EID4619

In a non-small cell lung cancer patient with acquired crizotinib resistance, the tumor had an EML4-ALK gene rearrangement (a known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation. … (full text at CIViC)

PMID 24675041 · Friboulet et al., 2014 · Open in CIViC

civic

Malignant Neoplasm8
ALK G1269A AND NPM1::ALK Fusion	Alectinib	Predictive	D	Supports Resistance	2	submitted	EID12664 In an in vitro study, a FL5.12 cell line expressing NPM-ALK and an ALK G1269A co-mutation, demonstrated increased resistance to alectinib treatment (IC50: 89.27 nmol/L), as compared to FL5.12 cells ex… (full text at CIViC) PMID 27009859 · Amin et al., 2016 · Open in CIViC	civic
ALK G1269A AND v::ALK Fusion	Alectinib	Predictive	D	Supports Resistance	3	accepted	EID1354 EML4-ALK with ALK G1269A mutation was tested for sensitivity to alectinib using Ba/F3 cells. In Ba/F3 cells with ectopic EML4-ALK variant 1 G1269A, IC50 of 84 nM was reported with alectinib, which was… (full text at CIViC) PMID 25727400 · Fontana et al., 2015 · Open in CIViC	civic
ALK G1269A AND v::ALK Fusion	Brigatinib	Predictive	D	Supports Sensitivity Response	2	accepted	EID1353 EML4-ALK with ALK G1269A has been seen in crizotinib resistant NSCLC, and this mutation was tested for Brigatinib sensitivity via ectopic expression in Ba/F3 cells, where half maximal inhibitory conce… (full text at CIViC) PMID 25727400 · Fontana et al., 2015 · Open in CIViC	civic
ALK G1269A AND v::ALK Fusion	Ceritinib	Predictive	D	Supports Sensitivity Response	2	accepted	EID1355 EML4-ALK with G1269A mutation was tested for sensitivity to ceritinib via transduction into Ba/F3 cells and generation of survival curves varying ceritinib concentration. IC50 of 33 nM was seen, which… (full text at CIViC) PMID 25727400 · Fontana et al., 2015 · Open in CIViC	civic
EML4::ALK Fusion AND ALK G1269A	Alectinib	Predictive	D	Supports Resistance	2	submitted	EID12669 In an in vitro study, a FL5.12 cell line expressing EML4-ALK (known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated increased resistance to alectinib treatment (IC50:… (full text at CIViC) PMID 27009859 · Amin et al., 2016 · Open in CIViC	civic
EML4::ALK Fusion AND ALK G1269A	AZD3463	Predictive	D	Does Not Support Resistance	2	submitted	EID12680 In an in vitro study, a FL5.12 cell line expressing EML4-ALK (known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated similar sensitivity to AZD3463 treatment (IC50: 11… (full text at CIViC) PMID 27009859 · Amin et al., 2016 · Open in CIViC	civic
EML4::ALK Fusion AND ALK G1269A	Brigatinib	Predictive	D	Does Not Support Resistance	2	submitted	EID12672 In an in vitro study, a FL5.12 cell line expressing EML4-ALK (known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated similar sensitivity to AP26113 treatment (IC50: 4.… (full text at CIViC) PMID 27009859 · Amin et al., 2016 · Open in CIViC	civic
EML4::ALK Fusion AND ALK G1269A	Crizotinib	Predictive	D	Supports Resistance	2	submitted	EID4621 In an in vitro study, a FL5.12 cell line expressing NPM1-ALK or EML4-ALK (known sensitizing alterations to crizotinib) and an ALK G1269A co-mutation, demonstrated resistance to crizotinib treatment (I… (full text at CIViC) PMID 27009859 · Amin et al., 2016 · Open in CIViC	civic

Malignant Neoplasm8

ALK G1269A AND NPM1::ALK Fusion

Alectinib

Predictive

Supports Resistance

submitted

EID12664

In an in vitro study, a FL5.12 cell line expressing NPM-ALK and an ALK G1269A co-mutation, demonstrated increased resistance to alectinib treatment (IC50: 89.27 nmol/L), as compared to FL5.12 cells ex… (full text at CIViC)

PMID 27009859 · Amin et al., 2016 · Open in CIViC

civic

ALK G1269A AND v::ALK Fusion

Alectinib

Predictive

Supports Resistance

accepted

EID1354

EML4-ALK with ALK G1269A mutation was tested for sensitivity to alectinib using Ba/F3 cells. In Ba/F3 cells with ectopic EML4-ALK variant 1 G1269A, IC50 of 84 nM was reported with alectinib, which was… (full text at CIViC)

PMID 25727400 · Fontana et al., 2015 · Open in CIViC

civic

ALK G1269A AND v::ALK Fusion

Brigatinib

Predictive

Supports Sensitivity Response

accepted

EID1353

EML4-ALK with ALK G1269A has been seen in crizotinib resistant NSCLC, and this mutation was tested for Brigatinib sensitivity via ectopic expression in Ba/F3 cells, where half maximal inhibitory conce… (full text at CIViC)

PMID 25727400 · Fontana et al., 2015 · Open in CIViC

civic

ALK G1269A AND v::ALK Fusion

Ceritinib

Predictive

Supports Sensitivity Response

accepted

EID1355

EML4-ALK with G1269A mutation was tested for sensitivity to ceritinib via transduction into Ba/F3 cells and generation of survival curves varying ceritinib concentration. IC50 of 33 nM was seen, which… (full text at CIViC)

PMID 25727400 · Fontana et al., 2015 · Open in CIViC

civic

EML4::ALK Fusion AND ALK G1269A

Alectinib

Predictive

Supports Resistance

submitted

EID12669

In an in vitro study, a FL5.12 cell line expressing EML4-ALK (known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated increased resistance to alectinib treatment (IC50:… (full text at CIViC)

PMID 27009859 · Amin et al., 2016 · Open in CIViC

civic

EML4::ALK Fusion AND ALK G1269A

AZD3463

Predictive

Does Not Support Resistance

submitted

EID12680

In an in vitro study, a FL5.12 cell line expressing EML4-ALK (known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated similar sensitivity to AZD3463 treatment (IC50: 11… (full text at CIViC)

PMID 27009859 · Amin et al., 2016 · Open in CIViC

civic

EML4::ALK Fusion AND ALK G1269A

Brigatinib

Predictive

Does Not Support Resistance

submitted

EID12672

In an in vitro study, a FL5.12 cell line expressing EML4-ALK (known sensitizing alteration to crizotinib) and an ALK G1269A co-mutation, demonstrated similar sensitivity to AP26113 treatment (IC50: 4.… (full text at CIViC)

PMID 27009859 · Amin et al., 2016 · Open in CIViC

civic

EML4::ALK Fusion AND ALK G1269A

Crizotinib

Predictive

Supports Resistance

submitted

EID4621

In an in vitro study, a FL5.12 cell line expressing NPM1-ALK or EML4-ALK (known sensitizing alterations to crizotinib) and an ALK G1269A co-mutation, demonstrated resistance to crizotinib treatment (I… (full text at CIViC)

PMID 27009859 · Amin et al., 2016 · Open in CIViC

civic

Evidence by cancer (18 items)

Clinical significance (1)