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    1. karim2001khoury 19 Feb 2026
      A Functional Dissection of PTEN N-Terminus: Implications in PTEN Subcellular Targeting and Tumor Suppressor Activity

      [Paper-level Aggregated] PMCID: PMC4398541

      Evidence Type(s): Functional, Oncogenic, Predictive

      Justification: Functional: The text describes a functional analysis of various PTEN mutations, assessing their impact on subcellular localization and PIP3 phosphatase activity, indicating their functional roles in PTEN's tumor suppressor activity. Oncogenic: The mutations are associated with tumorigenesis, as they are described as "tumor-associated" and their effects on PTEN function suggest a potential role in cancer development. Predictive: The analysis of specific mutations and their effects on PTEN activity and localization can predict the functional consequences of these mutations in a clinical context, potentially guiding therapeutic decisions.

      Gene→Variant (gene-first): PTEN(5728):A34D PTEN(5728):A34V PTEN(5728):D24Y PTEN(5728):G36R PTEN(5728):I33S PTEN(5728):K13E PTEN(5728):L23F PTEN(5728):L42P PTEN(5728):M35R PTEN(5728):R15I PTEN(5728):R15S PTEN(5728):S10N PTEN(5728):Y16C PTEN(5728):A39V PTEN(5728):Ala residues were mutated to Val ACTG1(71):D19A PTEN(5728):D24A PTEN(5728):E18A PTEN(5728):F21A PTEN(5728):G20A PTEN(5728):I28A PTEN(5728):I32A PTEN(5728):I33A PTEN(5728):K13A PTEN(5728):L42A PTEN(5728):M35A PTEN(5728):N12A PTEN(5728):N31A PTEN(5728):P30A AAA1(100329167):R14A PTEN(5728):R15A PTEN(5728):Y16A PTEN(5728):Y27A PTEN(5728):I5A PTEN(5728):K6A PTEN(5728):P38A PTEN(5728):Q17A PTEN(5728):S10A AAA1(100329167):Arg14 PTEN(5728):Arg15 PTEN(5728):K13R PTEN(5728):Lys13 AAA1(100329167):R14K PTEN(5728):R15K

      Genes: PTEN(5728) ACTG1(71) AAA1(100329167)

      Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C A39V Ala residues were mutated to Val D19A D24A E18A F21A G20A I28A I32A I33A K13A L42A M35A N12A N31A P30A R14A R15A Y16A Y27A I5A K6A P38A Q17A S10A Arg14 Arg15 K13R Lys13 R14K R15K

      CIViC paper-level aggregated PMC4398541
    2. karim2001khoury 19 Feb 2026
      To test the function on mammalian cells of PTEN N-terminal mutations displaying distinctive nuclear accumulation, stable human osteosarcoma U2OS Tet-Off cell lines expressing PTEN 1-375/L23F and 1-375/N31A mutations were

      [Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the L23F and N31A mutations alter the molecular function of PTEN, specifically its PIP3 catalytic activity and nuclear accumulation, indicating changes in biochemical function. Oncogenic: The results indicate that the L23F mutation leads to a complete loss-of-function in terms of cell growth inhibitory capacity, suggesting that it contributes to tumor development or progression.

      Gene→Variant (gene-first): 5728:L23F 5728:N31A

      Genes: 5728

      Variants: L23F N31A

      CIViC paragraph-level PMC4398541 Functional Oncogenic
    3. karim2001khoury 19 Feb 2026
      Since specific residues from the positively charged motif at the PTEN N-terminus NLS (Lys13Arg14Arg15; KRR motif) (Fig 2A) are important for nuclear localization or phosphatase activity in vivo, we performed additional a

      [Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how specific mutations (K13R, R14K, K13E, etc.) affect the molecular functions of PTEN, including its nuclear localization and phosphatase activity, indicating alterations in biochemical function. Oncogenic: The mutations are described in the context of their role in PTEN's function related to tumor development, particularly in terms of phosphatase activity and localization, which are critical for its tumor suppressor role.

      Gene→Variant (gene-first): 100329167:Arg14 5728:Arg15 5728:K13A 5728:K13E 5728:K13R 5728:Lys13 100329167:R14A 100329167:R14K 5728:R15A 5728:R15K

      Genes: 100329167 5728

      Variants: Arg14 Arg15 K13A K13E K13R Lys13 R14A R14K R15A R15K

      CIViC paragraph-level PMC4398541 Functional Oncogenic
    4. karim2001khoury 19 Feb 2026
      Regarding the PIP3 phosphatase activity of the PTEN mutations in the yeast in vivo assay, a set of mutations, including R15A, Y16A, D24A, I32A, M35A, P38A, and A39V, displayed complete loss-of-function, whereas the rest

      [Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how specific mutations alter PTEN's phosphatase activity and nuclear accumulation, indicating that these variants affect molecular function. Oncogenic: The context implies that the mutations contribute to the functional behavior of PTEN, which is known to be involved in tumor suppression, suggesting a role in tumor development or progression.

      Gene→Variant (gene-first): 5728:A39V 5728:D24A 5728:I32A 5728:I33A 5728:I5A 5728:K6A 5728:L42A 5728:M35A 5728:P38A 5728:Q17A 5728:R15A 5728:S10A 5728:Y16A

      Genes: 5728

      Variants: A39V D24A I32A I33A I5A K6A L42A M35A P38A Q17A R15A S10A Y16A

      CIViC paragraph-level PMC4398541 Functional Oncogenic
    5. karim2001khoury 19 Feb 2026
      To further dissect the involvement of PTEN N-terminal region in its function, we performed a full Ala-scanning mutagenesis of the PTEN region from residue 2 to residue 43 (Ala residues were mutated to Val). The mutated r

      [Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how specific mutations in the PTEN N-terminal region alter its subcellular localization, indicating that these variants affect the molecular function of the protein.

      Gene→Variant (gene-first): 5728:A39V 5728:Ala residues were mutated to Val 71:D19A 5728:D24A 5728:E18A 5728:F21A 5728:G20A 5728:I28A 5728:I32A 5728:I33A 5728:K13A 5728:L42A 5728:M35A 5728:N12A 5728:N31A 5728:P30A 100329167:R14A 5728:R15A 5728:Y16A 5728:Y27A

      Genes: 5728 71 100329167

      Variants: A39V Ala residues were mutated to Val D19A D24A E18A F21A G20A I28A I32A I33A K13A L42A M35A N12A N31A P30A R14A R15A Y16A Y27A

      CIViC paragraph-level PMC4398541 Functional
    6. karim2001khoury 19 Feb 2026
      Next, the PIP3 phosphatase activity of the tumor-associated N-terminal PTEN mutations was assessed using the S. cerevisiae heterologous reconstitution system. In these experiments, the mutations were tested in a PTEN 1-4

      [Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations alter the PIP3 phosphatase activity of PTEN, indicating that these variants affect molecular function. Oncogenic: The variants are described as "tumor-associated" and their effects on PTEN activity suggest a contribution to tumor development or progression.

      Gene→Variant (gene-first): 5728:A34D 5728:A34V 5728:D24Y 5728:G36R 5728:I33S 5728:K13E 5728:L23F 5728:L42P 5728:M35R 5728:R15I 5728:R15S 5728:S10N 5728:Y16C

      Genes: 5728

      Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C

      CIViC paragraph-level PMC4398541 Functional Oncogenic
    7. karim2001khoury 19 Feb 2026
      The PTEN N-terminal region contains motifs important for PTEN subcellular localization and function (Fig 2A). To analyze the contribution of this region to PTEN tumor suppressor function in vivo, we performed a functiona

      [Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how various PTEN mutations alter the nuclear/cytosolic localization and function of the protein, indicating changes in molecular or biochemical function.

      Gene→Variant (gene-first): 5728:A34D 5728:A34V 5728:D24Y 5728:G36R 5728:I33S 5728:K13E 5728:L23F 5728:L42P 5728:M35R 5728:R15I 5728:R15S 5728:S10N 5728:Y16C

      Genes: 5728

      Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C

      CIViC paragraph-level PMC4398541 Functional
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    pmc.ncbi.nlm.nih.gov/articles/PMC4398541/pdf/pone.0119287.pdf