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    1. karim2001khoury 19 Feb 2026
      Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

      [Paper-level Aggregated] PMCID: PMC7190743

      Evidence Type(s): Oncogenic, Functional, Predictive, Predisposing

      Justification: Oncogenic: The text mentions that certain PTEN variants, including C124S and G129E, have been found in somatic cancer, indicating their potential role in cancer development. Functional: The study assesses the functionality of various PTEN variants through multiple assays, demonstrating that many variants exhibit loss of function (LoF) or gain of function (GoF) phenotypes, impacting cellular processes such as synaptogenesis and insulin signaling. Predictive: The classification of variants as Pathogenic or Likely Pathogenic based on their functional impact suggests that these variants can predict disease outcomes, particularly in relation to ASD and other disorders. Predisposing: The identification of variants associated with ASD, intellectual disability, and developmental delay indicates that these genetic alterations may predispose individuals to these conditions.

      Gene→Variant (gene-first): PTEN(5728):A126D PTEN(5728):A126P PTEN(5728):C124S PTEN(5728):G129E PTEN(5728):H123Q PTEN(5728):P354Q PTEN(5728):P38H PTEN(5728):Q396R PTEN(5728):R130L PTEN(5728):R130Q PTEN(5728):A79T PTEN(5728):D268E PTEN(5728):G132D PTEN(5728):I101T PTEN(5728):T167N PTEN(5728):Y176C PTEN(5728):C211W PTEN(5728):E157G PTEN(5728):I135V PTEN(5728):I203V PTEN(5728):I400V PTEN(5728):K342N PTEN(5728):K402N PTEN(5728):L345V PTEN(5728):L70V PTEN(5728):M35V PTEN(5728):N117S PTEN(5728):N228S PTEN(5728):N340D PTEN(5728):N340H PTEN(5728):N356D PTEN(5728):Q298E PTEN(5728):S229T PTEN(5728):T202I PTEN(5728):T78A PTEN(5728):W274L PTEN(5728):Y180H PTEN(5728):Y65C PTEN(5728):R130X PTEN(5728):R335X PTEN(5728):Y138L PTEN(5728):H93Y PTEN(5728):R14G PTEN(5728):R15S

      Genes: PTEN(5728)

      Variants: A126D A126P C124S G129E H123Q P354Q P38H Q396R R130L R130Q A79T D268E G132D I101T T167N Y176C C211W E157G I135V I203V I400V K342N K402N L345V L70V M35V N117S N228S N340D N340H N356D Q298E S229T T202I T78A W274L Y180H Y65C R130X R335X Y138L H93Y R14G R15S

      CIViC paper-level aggregated PMC7190743
    2. karim2001khoury 19 Feb 2026
      Of the 106 variants tested, we classify 50 as Pathogenic, including 31 ASD. We further classify 10 variants, including 4 ASD, as Likely Pathogenic. We consider 24 variants to be Likely Benign, including 3 ASD: P354Q, T20

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 25

      Evidence Type(s): Diagnostic

      Justification: Diagnostic: The passage discusses the classification of variants as Pathogenic and Likely Pathogenic, indicating their association with specific diseases or subtypes, which aligns with the definition of diagnostic evidence.

      Gene→Variant (gene-first): 5728:A79T 5728:C211W 5728:E157G 5728:H123Q 5728:I135V 5728:I203V 5728:I400V 5728:K342N 5728:K402N 5728:L345V 5728:L70V 5728:M35V 5728:N117S 5728:N228S 5728:N340D 5728:N340H 5728:N356D 5728:P354Q 5728:Q298E 5728:S229T 5728:T202I 5728:T78A 5728:W274L 5728:Y176C 5728:Y180H 5728:Y65C

      Genes: 5728

      Variants: A79T C211W E157G H123Q I135V I203V I400V K342N K402N L345V L70V M35V N117S N228S N340D N340H N356D P354Q Q298E S229T T202I T78A W274L Y176C Y180H Y65C

      CIViC paragraph-level PMC7190743 Diagnostic
    3. karim2001khoury 19 Feb 2026
      PTEN functions as a negative regulator of the PI3-AKT signaling pathway by decreasing the pool of available PI(3,4,5)P3 via its lipid phosphatase activity, causing a reduction in the level of activated, phosphorylated AK

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how various PTEN variants, including A126D, A126P, C124S, G129E, H123Q, P354Q, P38H, Q396R, R130L, and R130Q, alter the molecular function of PTEN by affecting pAKT levels, indicating changes in biochemical activity. Oncogenic: The variants are described in the context of their effects on the PI3-AKT signaling pathway and their ability to exhibit loss of function (LoF) or gain of function (GoF), which are indicative of their roles in tumor development or progression.

      Gene→Variant (gene-first): 5728:A126D 5728:A126P 5728:C124S 5728:G129E 5728:H123Q 5728:P354Q 5728:P38H 5728:Q396R 5728:R130L 5728:R130Q

      Genes: 5728

      Variants: A126D A126P C124S G129E H123Q P354Q P38H Q396R R130L R130Q

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    4. karim2001khoury 19 Feb 2026
      To identify molecular mechanisms underlying variable effects of MS variants, we measured impact on protein stability, a known mechanism of PTEN dysfunction. We measured PTEN protein abundance for WT and 97 variants teste

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants affect protein stability and abundance, indicating that they alter molecular function, which is supported by the use of western blot analysis and flow cytometry to measure these changes.

      Gene→Variant (gene-first): 5728:H93Y 5728:P354Q 5728:R130L 5728:R14G 5728:R15S 5728:T78A

      Genes: 5728

      Variants: H93Y P354Q R130L R14G R15S T78A

      CIViC paragraph-level PMC7190743 Functional
    5. karim2001khoury 19 Feb 2026
      Since ASD is a behaviorally diagnosed disorder, and deficits in sensory processing are a core feature of ASD present in >95% of cases, we tested the effects of PTEN variants on sensorimotor neural circuit function in an

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how PTEN variants affect sensorimotor neural circuit function and chemotaxis in C. elegans, indicating that these variants alter molecular or biochemical function. Oncogenic: The context of the passage suggests that the PTEN variants are involved in a pathway related to tumor development or progression, particularly given the focus on mutations in a cancer-related gene.

      Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:P354Q 5728:T167N 5728:Y176C

      Genes: 5728

      Variants: A79T C124S D268E G132D P354Q T167N Y176C

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    6. karim2001khoury 19 Feb 2026
      Aberrant neuronal morphology and excitatory/inhibitory synapse balance are hallmarks of ASD, and ASD rodent models. Reducing PTEN expression results in increased neuronal growth, with larger soma size, increased dendriti

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how various PTEN variants, including C124S, I101T, G132D, D268E, and A79T, alter neuronal growth processes and synapse density, indicating that these variants affect molecular or biochemical functions in neuronal cultures. Oncogenic: The passage mentions that the PHTS variant A79T exhibits a gain-of-function (GoF) phenotype in axonal growth, suggesting that it contributes to tumor development or progression in the context of its association with ASD.

      Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:I101T

      Genes: 5728

      Variants: A79T C124S D268E G132D I101T

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    7. karim2001khoury 19 Feb 2026
      We generated 88 transgenic lines of Drosophila melanogaster expressing WT human PTEN and 86 PTEN variants, each integrated into the attP2 locus, with attP2 used as an empty vector (EV) control, allowing quantitative comp

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how various PTEN variants, including C124S, G129E, N117S, and Q298E, alter developmental rates in Drosophila, indicating that these variants affect molecular or biochemical function related to insulin signaling and eclosion timing. Oncogenic: The mention of the known gain-of-function variant 4A inducing lethality suggests that some variants contribute to tumor development or progression, aligning with oncogenic behavior.

      Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:N117S 5728:Q298E

      Genes: 5728

      Variants: C124S G129E N117S Q298E

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    8. karim2001khoury 19 Feb 2026
      We took advantage of the high-throughput capacity of the Saccharomyces cerevisiae synthetic dosage lethality screen as an unbiased assay to identify genetic interactions of PTEN. By overexpressing human WT PTEN (WT), emp

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the C124S variant alters molecular interactions and functions within the context of PI3P metabolism and signaling, indicating a change in biochemical activity. Oncogenic: The C124S variant is described in the context of genetic interactions that may contribute to tumor development or progression, as it is involved in a synthetic dosage lethality screen related to PTEN's role in cancer biology.

      Gene→Variant (gene-first): 5728:C124S

      Genes: 5728

      Variants: C124S

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    9. karim2001khoury 19 Feb 2026
      We selected PTEN MS and nonsense (NS) mutations identified in individuals with ASD, intellectual disability (ID), developmental delay (DD), somatic cancer and PHTS, as well as variants found among the general population

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Diagnostic, Oncogenic, Functional

      Justification: Diagnostic: The passage discusses the classification of variants, including C124S, G129E, R130X, and R335X, in relation to their association with conditions such as ASD, PHTS, and somatic cancer, indicating their role in defining or confirming these diseases. Oncogenic: The passage mentions that C124S and G129E have been found in somatic cancer, indicating that these variants contribute to tumor development or progression. Functional: The passage describes several variants, including C124S and G129E, as having well-characterized disruptions on protein function, indicating that they alter molecular or biochemical function.

      Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:R130X 5728:R335X 5728:Y138L

      Genes: 5728

      Variants: C124S G129E R130X R335X Y138L

      CIViC paragraph-level PMC7190743 Diagnostic Oncogenic Functional
    10. karim2001khoury 19 Feb 2026
      Of the 106 variants tested, we classify 50 as Pathogenic, including 31 ASD. We further classify 10 variants, including 4 ASD, as Likely Pathogenic. We consider 24 variants to be Likely Benign, including 3 ASD: P354Q, T20

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 25

      Evidence Type(s): Diagnostic

      Justification: Diagnostic: The passage discusses the classification of variants as Pathogenic and Likely Pathogenic, indicating their association with specific diseases or subtypes, which aligns with the definition of diagnostic evidence.

      Gene→Variant (gene-first): 5728:A79T 5728:C211W 5728:E157G 5728:H123Q 5728:I135V 5728:I203V 5728:I400V 5728:K342N 5728:K402N 5728:L345V 5728:L70V 5728:M35V 5728:N117S 5728:N228S 5728:N340D 5728:N340H 5728:N356D 5728:P354Q 5728:Q298E 5728:S229T 5728:T202I 5728:T78A 5728:W274L 5728:Y176C 5728:Y180H 5728:Y65C

      Genes: 5728

      Variants: A79T C211W E157G H123Q I135V I203V I400V K342N K402N L345V L70V M35V N117S N228S N340D N340H N356D P354Q Q298E S229T T202I T78A W274L Y176C Y180H Y65C

      CIViC paragraph-level PMC7190743 Diagnostic
    11. karim2001khoury 19 Feb 2026
      PTEN functions as a negative regulator of the PI3-AKT signaling pathway by decreasing the pool of available PI(3,4,5)P3 via its lipid phosphatase activity, causing a reduction in the level of activated, phosphorylated AK

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 16

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how various PTEN variants, including A126D, A126P, C124S, G129E, H123Q, P354Q, P38H, Q396R, R130L, and R130Q, alter the molecular function of PTEN by affecting pAKT levels, indicating changes in biochemical activity. Oncogenic: The variants are described in the context of their effects on the PI3-AKT signaling pathway and their ability to exhibit loss of function (LoF) or gain of function (GoF), which are indicative of their roles in tumor development or progression.

      Gene→Variant (gene-first): 5728:A126D 5728:A126P 5728:C124S 5728:G129E 5728:H123Q 5728:P354Q 5728:P38H 5728:Q396R 5728:R130L 5728:R130Q

      Genes: 5728

      Variants: A126D A126P C124S G129E H123Q P354Q P38H Q396R R130L R130Q

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    12. karim2001khoury 19 Feb 2026
      To identify molecular mechanisms underlying variable effects of MS variants, we measured impact on protein stability, a known mechanism of PTEN dysfunction. We measured PTEN protein abundance for WT and 97 variants teste

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 14

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants affect protein stability and abundance, indicating that they alter molecular function, which is supported by the use of western blot analysis and flow cytometry to measure these changes.

      Gene→Variant (gene-first): 5728:H93Y 5728:P354Q 5728:R130L 5728:R14G 5728:R15S 5728:T78A

      Genes: 5728

      Variants: H93Y P354Q R130L R14G R15S T78A

      CIViC paragraph-level PMC7190743 Functional
    13. karim2001khoury 19 Feb 2026
      Since ASD is a behaviorally diagnosed disorder, and deficits in sensory processing are a core feature of ASD present in >95% of cases, we tested the effects of PTEN variants on sensorimotor neural circuit function in an

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 12

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how PTEN variants affect sensorimotor neural circuit function and chemotaxis in C. elegans, indicating that these variants alter molecular or biochemical function. Oncogenic: The context of the passage suggests that the PTEN variants are involved in a pathway related to tumor development or progression, particularly given the focus on mutations in a cancer-related gene.

      Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:P354Q 5728:T167N 5728:Y176C

      Genes: 5728

      Variants: A79T C124S D268E G132D P354Q T167N Y176C

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    14. karim2001khoury 19 Feb 2026
      Aberrant neuronal morphology and excitatory/inhibitory synapse balance are hallmarks of ASD, and ASD rodent models. Reducing PTEN expression results in increased neuronal growth, with larger soma size, increased dendriti

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how various PTEN variants, including C124S, I101T, G132D, D268E, and A79T, alter neuronal growth processes and synapse density, indicating that these variants affect molecular or biochemical functions in neuronal cultures. Oncogenic: The passage mentions that the PHTS variant A79T exhibits a gain-of-function (GoF) phenotype in axonal growth, suggesting that it contributes to tumor development or progression in the context of its association with ASD.

      Gene→Variant (gene-first): 5728:A79T 5728:C124S 5728:D268E 5728:G132D 5728:I101T

      Genes: 5728

      Variants: A79T C124S D268E G132D I101T

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    15. karim2001khoury 19 Feb 2026
      We generated 88 transgenic lines of Drosophila melanogaster expressing WT human PTEN and 86 PTEN variants, each integrated into the attP2 locus, with attP2 used as an empty vector (EV) control, allowing quantitative comp

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how various PTEN variants, including C124S, G129E, N117S, and Q298E, alter developmental rates in Drosophila, indicating that these variants affect molecular or biochemical function related to insulin signaling and eclosion timing. Oncogenic: The mention of the known gain-of-function variant 4A inducing lethality suggests that some variants contribute to tumor development or progression, aligning with oncogenic behavior.

      Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:N117S 5728:Q298E

      Genes: 5728

      Variants: C124S G129E N117S Q298E

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    16. karim2001khoury 19 Feb 2026
      We took advantage of the high-throughput capacity of the Saccharomyces cerevisiae synthetic dosage lethality screen as an unbiased assay to identify genetic interactions of PTEN. By overexpressing human WT PTEN (WT), emp

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the C124S variant alters molecular interactions and functions within the context of PI3P metabolism and signaling, indicating a change in biochemical activity. Oncogenic: The C124S variant is described in the context of genetic interactions that may contribute to tumor development or progression, as it is involved in a synthetic dosage lethality screen related to PTEN's role in cancer biology.

      Gene→Variant (gene-first): 5728:C124S

      Genes: 5728

      Variants: C124S

      CIViC paragraph-level PMC7190743 Functional Oncogenic
    17. karim2001khoury 19 Feb 2026
      We selected PTEN MS and nonsense (NS) mutations identified in individuals with ASD, intellectual disability (ID), developmental delay (DD), somatic cancer and PHTS, as well as variants found among the general population

      [Paragraph-level] PMCID: PMC7190743 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Diagnostic, Oncogenic, Functional

      Justification: Diagnostic: The passage discusses the classification of variants, including C124S, G129E, R130X, and R335X, in relation to their association with conditions such as ASD, PHTS, and somatic cancer, indicating their role in defining or confirming these diseases. Oncogenic: The passage mentions that C124S and G129E have been found in somatic cancer, indicating that these variants contribute to tumor development or progression. Functional: The passage describes several variants, including C124S and G129E, as having well-characterized disruptions on protein function, indicating that they alter molecular or biochemical function.

      Gene→Variant (gene-first): 5728:C124S 5728:G129E 5728:R130X 5728:R335X 5728:Y138L

      Genes: 5728

      Variants: C124S G129E R130X R335X Y138L

      CIViC paragraph-level PMC7190743 Diagnostic Oncogenic Functional
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    pmc.ncbi.nlm.nih.gov/articles/PMC7190743/pdf/41467_2020_Article_15943.pdf