ERBB2 V777L

Loading variant…

Molecular profile	Therapy	Type	Level	Direction · significance	Rating (1–5)	Status	Evidence	Source
HER2-Positive Breast Carcinoma1
ERBB2 V777L	Trastuzumab + Trastuzumab EmtansineSubstitutes	Predictive	C	Supports Resistance	3	submitted	EID5817 In a cohort of 205 Her2-receptor amplified breast cancers, 20 experienced recurrence after trastuzumab therapy. Of the 20 recurrent cases, only six patients had metastatic sites, excluding brain metas… (full text at CIViC) PMID 27900589 · Hirotsu et al., 2017 · Open in CIViC	civic
Malignant Breast Neoplasm2
ERBB2 V777L	Afatinib	Predictive	C	Supports Sensitivity Response	1	accepted	EID11690 In this phase II NCI-MATCH trial, a patient with ER+ invasive ductal breast cancer with ERBB2 V777L mutation was treated with afatinib. A RECIST response was reported in the patient, however, it wasn'…

Molecular profile

Therapy

Type

Level

Direction · significance

Rating (1–5)

Status

Evidence

Source

HER2-Positive Breast Carcinoma1

ERBB2 V777L

Trastuzumab + Trastuzumab EmtansineSubstitutes

Predictive

Supports Resistance

submitted

EID5817

In a cohort of 205 Her2-receptor amplified breast cancers, 20 experienced recurrence after trastuzumab therapy. Of the 20 recurrent cases, only six patients had metastatic sites, excluding brain metas… (full text at CIViC)

PMID 27900589 · Hirotsu et al., 2017 · Open in CIViC

civic

Malignant Breast Neoplasm2

ERBB2 V777L

Afatinib

Predictive

Supports Sensitivity Response

accepted

EID11690

In this phase II NCI-MATCH trial, a patient with ER+ invasive ductal breast cancer with ERBB2 V777L mutation was treated with afatinib. A RECIST response was reported in the patient, however, it wasn'…

Variation	Clinical significance	Review status	Stars	Conditions	Origin	Submitters	Last evaluated	Source
44991	Uncertain significance	criteria provided, single submitter	1	Neoplasm; Neurofibroma	somatic	3	Aug 17, 2010	clinvar

Variation

Clinical significance

Review status

Stars

Conditions

Origin

Submitters

Last evaluated

Source

44991

Uncertain significance

criteria provided, single submitter

Neoplasm; Neurofibroma

somatic

Aug 17, 2010

clinvar

Malignant Colon Neoplasm1
ERBB2 V777L	Lapatinib + Neratinib + TrastuzumabCombination	Predictive	D	Supports Sensitivity Response	4	accepted	EID1177 Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with tras… (full text at CIViC) PMID 26243863 · Kavuri et al., 2015 · Open in CIViC	civic

Malignant Colon Neoplasm1

ERBB2 V777L

Lapatinib + Neratinib + TrastuzumabCombination

Predictive

Supports Sensitivity Response

accepted

EID1177

Colon cancer patient derived xenografts with HER2 mutations are sensitive to HER2 targeted drugs and the greatest tumor reduction was seen with the combination of a tyrosine kinase inhibitor with tras… (full text at CIViC)

PMID 26243863 · Kavuri et al., 2015 · Open in CIViC

civic

Malignant Colorectal Neoplasm1
ERBB2 V777L	Cetuximab	Predictive	D	Supports Resistance	3	accepted	EID4452 In an in vitro study, NCI-H508 cell lines expressing an ERBB2 V777L mutation demonstrated resistance to cetuximab treatment (IC50 >200 ug/ml) compared to NCI-H508 cells expressing ERBB2 wild-type (IC5… (full text at CIViC) PMID 26243863 · Kavuri et al., 2015 · Open in CIViC	civic

Malignant Colorectal Neoplasm1

ERBB2 V777L

Cetuximab

Predictive

Supports Resistance

accepted

EID4452

In an in vitro study, NCI-H508 cell lines expressing an ERBB2 V777L mutation demonstrated resistance to cetuximab treatment (IC50 >200 ug/ml) compared to NCI-H508 cells expressing ERBB2 wild-type (IC5… (full text at CIViC)

PMID 26243863 · Kavuri et al., 2015 · Open in CIViC

civic

Malignant Neoplasm4
ERBB2 V777L	Lapatinib	Predictive	D	Supports Sensitivity Response	2	accepted	EID9697 Ba/F3 cells expressing ERBB2 V777L were treated with lapatinib and showed an IC50 value of 27nM, compared to 30nM for wild-type ERBB2 cells. The authors considered V777L as lapatinib-sensitive. PMID 22046346 · Kancha et al., 2011 · Open in CIViC	civic
ERBB2 V777L	Neratinib	Predictive	B	Does Not Support Sensitivity Response	3	submitted	EID12106 In the SUMMIT basket trial (NCT01953926) patients with solid tumors of various histologies harboring mutations of either HER2 or HER3 were enrolled and treated with the pan-HER kinase inhibitor nerati… (full text at CIViC) PMID 29420467 · Hyman et al., 2018 · Open in CIViC	civic
ERBB2 V777L	Afatinib + Lapatinib + Neratinib + OsimertinibSubstitutes	Predictive	D	Supports Sensitivity Response	3	submitted	EID12101 Ba/F3 mouse lymphoid cells expressing wild-type or V777L mutant HER2 were treated with afatinib, neratinib, osimertinib or DMSO (vehicle) for 72 hours, at which time viable cells were measured using t… (full text at CIViC) PMID 29967253 · Nagano et al., 2018 · Open in CIViC	civic
ERBB2 V777L	Trastuzumab	Predictive	D	Supports Resistance	3	submitted	EID12102 Ba/F3 mouse lymphoid cells expressing wild-type or V777L mutant HER2 were treated with afatinib, neratinib, osimertinib or DMSO (vehicle) for 72 hours, at which time viable cells were measured using t… (full text at CIViC) PMID 29967253 · Nagano et al., 2018 · Open in CIViC	civic

Malignant Neoplasm4

ERBB2 V777L

Lapatinib

Predictive

Supports Sensitivity Response

accepted

EID9697

Ba/F3 cells expressing ERBB2 V777L were treated with lapatinib and showed an IC50 value of 27nM, compared to 30nM for wild-type ERBB2 cells. The authors considered V777L as lapatinib-sensitive.

PMID 22046346 · Kancha et al., 2011 · Open in CIViC

civic

ERBB2 V777L

Neratinib

Predictive

Does Not Support Sensitivity Response

submitted

EID12106

In the SUMMIT basket trial (NCT01953926) patients with solid tumors of various histologies harboring mutations of either HER2 or HER3 were enrolled and treated with the pan-HER kinase inhibitor nerati… (full text at CIViC)

PMID 29420467 · Hyman et al., 2018 · Open in CIViC

civic

ERBB2 V777L

Afatinib + Lapatinib + Neratinib + OsimertinibSubstitutes

Predictive

Supports Sensitivity Response

submitted

EID12101

Ba/F3 mouse lymphoid cells expressing wild-type or V777L mutant HER2 were treated with afatinib, neratinib, osimertinib or DMSO (vehicle) for 72 hours, at which time viable cells were measured using t… (full text at CIViC)

PMID 29967253 · Nagano et al., 2018 · Open in CIViC

civic

ERBB2 V777L

Trastuzumab

Predictive

Supports Resistance

submitted

EID12102

PMID 29967253 · Nagano et al., 2018 · Open in CIViC

civic

Pancreatic Ductal Adenocarcinoma4
ERBB2 V777L	(oncogenic)	Oncogenic	D	Supports Oncogenicity	3	submitted	EID11559 HPNE cells infected with lentiviral vectors containing the variant did show significant phosphorylation of ERBB2 (Supplementary Figure 1) compared to WT (Figure 2A and B). The variant also exhibits an… (full text at CIViC) PMID 31046123 · Li et al., 2020 · Open in CIViC	civic
ERBB2 V777L	Neratinib	Predictive	D	Supports Sensitivity Response	3	submitted	EID11569 Neratinib suppresses anchorage-independent growth in transduced HPNE cells with the variant in a concentration-dependent manner (Figure 6B–C) with complete inhibition at a concentration of 0.5 µM (Fig… (full text at CIViC) PMID 31046123 · Li et al., 2020 · Open in CIViC	civic
ERBB2 V777L AND KRAS G12C	ARS-1620 + NeratinibCombination	Predictive	D	Supports Sensitivity Response	3	submitted	EID11572 When tested in MIAPaCa2 (PDAC cell line and KRAS G12C) cells, Neratinib and ARS-1620 strongly inhibit AKT and MAPK phosphorylation (Figure 6F). Also, MIAPaCa2 cell line with the variant in exposure to… (full text at CIViC) PMID 31046123 · Li et al., 2020 · Open in CIViC	civic
ERBB2 V777L AND KRAS G12D	(oncogenic)	Oncogenic	D	Supports Oncogenicity	3	submitted	EID11560 KRAS G12D-transformed HPNE cells with lentiviral vectors containing the variant significantly increased colony formation in number and size in soft agar compared to infected HPNE cells with the varian… (full text at CIViC) PMID 31046123 · Li et al., 2020 · Open in CIViC	civic

Pancreatic Ductal Adenocarcinoma4

ERBB2 V777L

(oncogenic)

Oncogenic

Supports Oncogenicity

submitted

EID11559

HPNE cells infected with lentiviral vectors containing the variant did show significant phosphorylation of ERBB2 (Supplementary Figure 1) compared to WT (Figure 2A and B). The variant also exhibits an… (full text at CIViC)

PMID 31046123 · Li et al., 2020 · Open in CIViC

civic

ERBB2 V777L

Neratinib

Predictive

Supports Sensitivity Response

submitted

EID11569

Neratinib suppresses anchorage-independent growth in transduced HPNE cells with the variant in a concentration-dependent manner (Figure 6B–C) with complete inhibition at a concentration of 0.5 µM (Fig… (full text at CIViC)

PMID 31046123 · Li et al., 2020 · Open in CIViC

civic

ERBB2 V777L AND KRAS G12C

ARS-1620 + NeratinibCombination

Predictive

Supports Sensitivity Response

submitted

EID11572

When tested in MIAPaCa2 (PDAC cell line and KRAS G12C) cells, Neratinib and ARS-1620 strongly inhibit AKT and MAPK phosphorylation (Figure 6F). Also, MIAPaCa2 cell line with the variant in exposure to… (full text at CIViC)

PMID 31046123 · Li et al., 2020 · Open in CIViC

civic

ERBB2 V777L AND KRAS G12D

(oncogenic)

Oncogenic

Supports Oncogenicity

submitted

EID11560

KRAS G12D-transformed HPNE cells with lentiviral vectors containing the variant significantly increased colony formation in number and size in soft agar compared to infected HPNE cells with the varian… (full text at CIViC)

PMID 31046123 · Li et al., 2020 · Open in CIViC

civic

Unmapped disease4unmapped disease
ERBB2 V777L	(functional)	Functional	D	Supports Gain Of Function	3	submitted	EID10023 A series of HER2 (ERBB2) mutations (G309A, D769H, D769Y, V777L, P780ins, V824I, R678Q, R896C, del755-759, and L755S) were functionally characterized and tested for sensitivity to lapatinib or neratini… (full text at CIViC) PMID 23220880 · Bose et al., 2013 · Open in CIViC	civic
ERBB2 V777L	(functional)	Functional	D	Supports Gain Of Function	5	submitted	EID12103 The V777L variant is located in the tyrosine kinase domain. In vitro kinase assays were conducted using recombinant expression of the isolated HER2 kinase domain. In this system wild-type (WT) HER2 sh… (full text at CIViC) PMID 23220880 · Bose et al., 2013 · Open in CIViC	civic
ERBB2 V777L	(functional)	Functional	D	Supports Gain Of Function	2	submitted	EID12104 Wild-type and V777L mutant HER2 proteins were ectopically expressed in NIH3T3 cells. The variant form of HER2 supported anchorage-independent growth in soft agar while the wild-type form did not and … (full text at CIViC) PMID 25720673 · Bellmunt et al., 2015 · Open in CIViC	civic
ERBB2 V777L	(functional)	Functional	D	Supports Gain Of Function	3	submitted	EID12105 To model HER2 missense mutations found in tumors without HER amplification, a targeted gene knock-in method was used to create isogenic MCF-10A and MCF7 human breast epithelial cell lines with a singl… (full text at CIViC) PMID 26508629 · Zabransky et al., 2015 · Open in CIViC	civic

Unmapped disease4unmapped disease

ERBB2 V777L

(functional)

Functional

Supports Gain Of Function

submitted

EID10023

A series of HER2 (ERBB2) mutations (G309A, D769H, D769Y, V777L, P780ins, V824I, R678Q, R896C, del755-759, and L755S) were functionally characterized and tested for sensitivity to lapatinib or neratini… (full text at CIViC)

PMID 23220880 · Bose et al., 2013 · Open in CIViC

civic

ERBB2 V777L

(functional)

Functional

Supports Gain Of Function

submitted

EID12103

The V777L variant is located in the tyrosine kinase domain. In vitro kinase assays were conducted using recombinant expression of the isolated HER2 kinase domain. In this system wild-type (WT) HER2 sh… (full text at CIViC)

PMID 23220880 · Bose et al., 2013 · Open in CIViC

civic

ERBB2 V777L

(functional)

Functional

Supports Gain Of Function

submitted

EID12104

Wild-type and V777L mutant HER2 proteins were ectopically expressed in NIH3T3 cells. The variant form of HER2 supported anchorage-independent growth in soft agar while the wild-type form did not and … (full text at CIViC)

PMID 25720673 · Bellmunt et al., 2015 · Open in CIViC

civic

ERBB2 V777L

(functional)

Functional

Supports Gain Of Function

submitted

EID12105

To model HER2 missense mutations found in tumors without HER amplification, a targeted gene knock-in method was used to create isogenic MCF-10A and MCF7 human breast epithelial cell lines with a singl… (full text at CIViC)

PMID 26508629 · Zabransky et al., 2015 · Open in CIViC

civic

Evidence by cancer (17 items)

Clinical significance (1)