Gene Variant Detail

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Gene PTEN
Variant H123Y
Impact List missense
Protein Effect unknown
Gene Variant Descriptions PTEN H123Y lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). The functional effect of H123Y is conflicting as it results in increased Akt activation and cell survival in culture in one study (PMID: 11448956), but suppresses Akt signaling similar to wild-type Pten in another study (PMID: 32704382), and demonstrates Pten protein stability similar to wild-type protein, however, fails to rescue spheroid formation (PMID: 32366478), and results in a loss of phosphatase activity (PMID: 9256433, PMID: 11448956, PMID: 29706350), and therefore, its effect on Pten protein function is unknown.
Associated Drug Resistance

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Transcript NM_000314.6
gDNA chr10:g.87933126C>T
cDNA c.367C>T
Protein p.H123Y
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_000314.6 chr10:g.87933126C>T c.367C>T p.H123Y RefSeq GRCh38/hg38
NM_000314 chr10:g.87933126C>T c.367C>T p.H123Y RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN mutant endometrial cancer resistant AZD6482 Preclinical Actionable In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to AZD6482 induced growth inhibition in culture (PMID: 23674493). 23674493
PTEN mutant head and neck squamous cell carcinoma resistant Taselisib Preclinical - Cell line xenograft Actionable In a preclinical study, head and neck squamous cell carcinoma cell lines and cell line xenograft models with PTEN alterations were resistant to the apoptotic effects of Taselisib (GDC-0032) (PMID: 26589432). 26589432
PTEN mutant breast cancer sensitive CUDC-907 Preclinical - Cell culture Actionable In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356). 22693356
PTEN mutant endometrial cancer resistant GSK2636771 Preclinical Actionable In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to GSK2636771 induced growth inhibition in culture (PMID: 23674493). 23674493
PTEN mutant endometrial cancer sensitive Everolimus Preclinical - Cell line xenograft Actionable In a preclinical study, Afinitor (everolimus) inhibited growth of endometrial cancer cells harboring a PTEN nonsense mutation in culture and in xenograft models (PMID: 22662154). 22662154
PTEN mutant endometrial cancer no benefit Temsirolimus Phase II Actionable In a retrospective study of a Phase II trial, mutation status of PTEN was not associated with progression-free survival or response rate in advanced endometrial cancer patients treated with Torisel (temsirolimus) (PMID: 27016228). 27016228
PTEN mutant glioblastoma no benefit Buparlisib + Capmatinib Phase Ib/II Actionable In a Phase Ib/II trial, combination of Buparlisib (BKM120) and Tabrecta (capmatinib) did not reach target exposure due to potential drug-drug interaction, and demonstrated minimal activity in patients with glioblastoma harboring PTEN alterations including deletion, mutation, or negative protein expression, therefore, Phase II of the trial was not initiated (PMID: 31776899; NCT01870726). 31776899
PTEN mutant lung adenocarcinoma no benefit Capivasertib Case Reports/Case Series Actionable In a Phase II trial (NLMT), Capivasertib (AZD5363) treatment did not result in a confirmed response (0/8) or durable clinical benefit (0/8) in patients with lung adenocarcinoma harboring mutations in PIK3CA, PTEN, or AKT, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). 32669708
PTEN mutant skin melanoma not applicable N/A Guideline Risk Factor Germline PTEN mutations or polymorphisms are associated with increased risk of developing single or multiple primary cutaneous melanomas (NCCN.org). detail...
PTEN mutant endometrial cancer resistant TGX-221 Preclinical Actionable In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to TGX-221 induced growth inhibition in culture (PMID: 23674493). 23674493
PTEN mutant uterine cancer sensitive GSK2256098 + Paclitaxel Preclinical Actionable In a preclinical study, uterine cancer cells harboring a PTEN mutation were more sensitive to the combination of GSK2256098 and Taxol (paclitaxel) than uterine cancer cells wild-type for PTEN, resulting in decreased tumor growth in culture and in mouse models (PMID: 25833835). 25833835
PTEN mutant endometrial cancer sensitive GDC-0980 Phase II Actionable In a Phase II trial, Apitolisib (GDC-0980) was poorly tolerated, but demonstrated efficacy in endometrial cancer patients harboring mutations in PIK3CA, PTEN, or AKT1 (J Clin Oncol 32:5s, 2014 (suppl; abstr 5513)). detail...
PTEN mutant uterine cancer sensitive GSK2256098 + Topotecan Preclinical Actionable In a preclinical study, uterine cancer cells harboring a PTEN mutation were more sensitive to the combination of GSK2256098 and Hycamtin (topotecan) than uterine cancer cells wild-type for PTEN, resulting in decreased tumor growth in culture and in mouse models (PMID: 25833835). 25833835
PTEN mutant endometrial cancer sensitive A66 + AZD6482 Preclinical Actionable In a preclinical study, A66 and AZD6482 combination treatment inhibited viability of endometrioid endometrial cancer cell lines harboring PTEN mutations in culture (PMID: 23674493). 23674493
PTEN mutant endometrial cancer sensitive A66 + GSK2636771 Preclinical Actionable In a preclinical study, A66 and GSK2636771 combination treatment inhibited viability of endometrioid endometrial cancer cell lines harboring PTEN mutations in culture (PMID: 23674493). 23674493
PTEN mutant gastrointestinal system cancer decreased response Pembrolizumab Clinical Study - Cohort Actionable In a retrospective analysis, patients with MSI high, dMMR gastrointestinal tumors including gastric (n=18), colorectal (n=17), cholangiocarcinoma (n=5), small intestine (n=2), pancreatic (n=2), and duodenal cancer (n=1) harboring PTEN mutations demonstrated a decreased objective response rate (21.4 vs 54.8%), overall survival (15.2 vs 25.7 mo), and progression-free survival (4.3 vs 15.6 mo) compared to PTEN-wild-type patients when treated with Keytruda (pembrolizumab) or Opdivo (nivolumab) (PMID: 33926917). 33926917
PTEN mutant melanoma sensitive BI-69A11 Preclinical - Cell line xenograft Actionable In a preclinical study, BI-69A11 resulted in antitumor activity in a melanoma cell line harboring a PTEN mutation, including induction of cell death in culture, and in xenograft models, tumor growth inhibition and tumor regression (PMID: 19175524). 19175524
PTEN mutant endometrial cancer resistant A66 Preclinical Actionable In a preclinical study, endometrioid endometrial cancer cell lines harboring PTEN mutations demonstrated resistance to A66 induced growth inhibition in culture (PMID: 23674493). 23674493
PTEN mutant breast cancer sensitive Sapanisertib Preclinical Actionable In a preclinical study, Sapanisertib (MLN0128) induced apoptosis and inhibited MTORC1 signaling in breast cancer cells harboring a PTEN mutation (PMID: 25261369). 25261369
PTEN mutant Advanced Solid Tumor no benefit Talazoparib Phase II Actionable In a Phase II trial, Talzenna (talazoparib) treatment did not result in significant clinical benefit in patients with advanced solid tumors harboring PTEN mutation or loss (by IHC), with one patient harboring a PTEN mutation achieved a prolonged stable disease as best response in a cohort of 13 patients (Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A096; NCT02286687). detail...
PTEN mutant breast cancer predicted - sensitive MS417 + Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) and MS417 in combination resulted in improved growth inhibition and increased cell death compared to either agent alone in a PTEN-mutant breast cancer cell line in culture (PMID: 26058079). 26058079
PTEN mutant endometrial cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 decreased growth of endometrial cancer cells harboring a PTEN nonsense mutation in culture and in xenograft models (PMID: 22662154). 22662154
PTEN mutant hepatocellular carcinoma decreased response Sorafenib Clinical Study - Cohort Actionable In a clinical case study, Nexavar (sorafenib) treatment of patients with hepatocellular carcinoma harboring Mtor pathway mutations in PIK3CA, PTEN, TSC2, or TSC1 (n=12), resulted in a lower disease control rate (8.3% vs. 40.2%), shorter progression-free survival (1.9 months vs. 5.3 months) and shorter overall survival (10.4 months vs. 17.9 months) compared to patients without mutations in this pathway (n=67) (PMID: 30373752; NCT01775072). 30373752
PTEN mutant gastrointestinal system cancer decreased response Nivolumab Clinical Study - Cohort Actionable In a retrospective analysis, patients with MSI high, dMMR gastrointestinal tumors including gastric (n=18), colorectal (n=17), cholangiocarcinoma (n=5), small intestine (n=2), pancreatic (n=2), and duodenal cancer (n=1) harboring PTEN mutations demonstrated a decreased objective response rate (21.4 vs 54.8%), overall survival (15.2 vs 25.7 mo), and progression-free survival (4.3 vs 15.6 mo) compared to PTEN-wild-type patients when treated with Keytruda (pembrolizumab) or Opdivo (nivolumab) (PMID: 33926917). 33926917
PTEN mutant uterine cancer sensitive GSK2256098 Preclinical Actionable In a preclinical study, uterine cancer cells harboring a PTEN mutation demonstrated sensitivity to GSK2256098, resulting in inhibition of Ptk2 (Fak) phosphorylation, decreased tumor growth, and apoptosis both in culture and in mouse models (PMID: 25833835). 25833835