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    1. karim2001khoury 19 Feb 2026
      The Impact of Point Mutations in the Human Androgen Receptor: Classification of Mutations on the Basis of Transcriptional Activity

      [Paper-level Aggregated] PMCID: PMC3293822

      Evidence Type(s): Oncogenic, Functional, Predisposing

      Justification: Oncogenic: The text discusses multiple mutations in the androgen receptor (AR) that are associated with prostate cancer (PCa), indicating that these mutations can drive cancer progression through altered transactivational activity and interaction with co-regulators. Functional: The evidence describes various mutations that exhibit changes in transactivational activity, including loss of function and gain of function, demonstrating their impact on AR function and signaling pathways relevant to prostate cancer. Predisposing: The mention of mutations such as K720E and R726L being implicated in a 6-fold increased risk of prostate cancer suggests a predisposition to developing the disease due to these genetic alterations.

      Gene→Variant (gene-first): CREBBP(1387):A234 AKT1(207):D221 AR(367):D528 AR(367):E198 FDXR(2232):G142 AR(367):G166 AR(367):G524 AR(367):L57 AR(367):M523 AR(367):M537 AR(367):P269 FDXR(2232):P340 AR(367):P390 AR(367):P514 MYBBP1A(10514):P515 AR(367):P533 AR(367):S296 AR(367):S334 CREBBP(1387):A234T AKT1(207):D221H AR(367):D528G AR(367):E198G AR(367):L57Q FDXR(2232):P340L NCOR1(9611):P504L AR(367):S296R AR(367):S334P BCL2A1(597):A586V AR(367):A587S NR3C1(2908):I672T NCOA2(10499):R629Q NCOA2(10499):T575A AR(367):A748V AR(367):A765T NCOR1(9611):K720E AR(367):L744F CREBBP(1387):M749 CREBBP(1387):M749I NCOR1(9611):M886V AR(367):N756D MYBBP1A(10514):Q798E AR(367):Q902R AR(367):R726L AR(367):S759P MYBBP1A(10514):V757A MYBBP1A(10514):V757I AR(367):Y763C AR(367):N756 AR(367):Q902 NCOR1(9611):lysine 720 AR(367):P269S NCOA2(10499):D879G AR(367):H874Y AR(367):Q919R AR(367):T877A FDXR(2232):G142V AR(367):G524D AR(367):M523V AR(367):M537V AR(367):P533S AR(367):P390L AR(367):G166S AR(367):M537R NR3C1(2908):I672 NCOA2(10499):R629 NCOA2(10499):T575 AR(367):K910R NCOR1(9611):M886 NCOR1(9611):M886I AR(367):P514S MYBBP1A(10514):S515G

      Genes: CREBBP(1387) AKT1(207) AR(367) FDXR(2232) MYBBP1A(10514) NCOR1(9611) BCL2A1(597) NR3C1(2908) NCOA2(10499)

      Variants: A234 D221 D528 E198 G142 G166 G524 L57 M523 M537 P269 P340 P390 P514 P515 P533 S296 S334 A234T D221H D528G E198G L57Q P340L P504L S296R S334P A586V A587S I672T R629Q T575A A748V A765T K720E L744F M749 M749I M886V N756D Q798E Q902R R726L S759P V757A V757I Y763C N756 Q902 lysine 720 P269S D879G H874Y Q919R T877A G142V G524D M523V M537V P533S P390L G166S M537R I672 R629 T575 K910R M886 M886I P514S S515G

      CIViC paper-level aggregated PMC3293822
    2. karim2001khoury 19 Feb 2026
      This analysis examined 45 single missense mutations detected in PCa with metastasis or high Gleason scores, and which extend along the entire length of the protein. Our sensitive assay system uncovered a previously unide

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 43

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how specific mutations (e.g., G142V, M523V, G524D, M537V) alter transactivational activity and regulatory element binding, indicating changes in molecular function. Oncogenic: The analysis of mutations in the context of prostate cancer (PCa) suggests that these variants contribute to tumor development or progression, particularly through their effects on transactivational activity related to cancer-related genes.

      Gene→Variant (gene-first): 2232:G142V 367:G524D 367:M523V 367:M537V 1387:M749I 10514:Q798E 10499:R629Q 10499:T575A

      Genes: 2232 367 1387 10514 10499

      Variants: G142V G524D M523V M537V M749I Q798E R629Q T575A

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    3. karim2001khoury 19 Feb 2026
      Mutations with no apparent change of activity from WT may be able to drive cancer progression though several diverse routes. These include altered binding to co-repressors or co-regulators e.g. M886I, regulatory element-

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 41

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses how the M886I variant may drive cancer progression through altered binding and other mechanisms, indicating its role in tumor development. Functional: The passage mentions that the M886I variant may alter binding to co-repressors or co-regulators, which suggests a change in molecular function.

      Gene→Variant (gene-first): 9611:M886I

      Genes: 9611

      Variants: M886I

      CIViC paragraph-level PMC3293822 Oncogenic Functional
    4. karim2001khoury 19 Feb 2026
      The LBD mutations had a greater dependence on the regulatory elements, emphasizing the importance of interdomain communication for receptor function. While the major losses of function seen with M749I at 10 nM DHT were c

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 36

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants M749I, Q798E, and H874Y alter the molecular function of the androgen receptor, specifically in terms of their constitutive activity and loss of function in response to DHT. Oncogenic: The passage indicates that the mutations M749I, Q798E, and H874Y may contribute to prostate cancer development and progression, particularly through their effects on androgen receptor signaling and activity.

      Gene→Variant (gene-first): 367:H874Y 1387:M749I 10514:Q798E

      Genes: 367 1387 10514

      Variants: H874Y M749I Q798E

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    5. karim2001khoury 19 Feb 2026
      Mutations within the DBD and hinge domains of the AR would be expected to have the greatest influence on regulating ARE binding and indeed, the profile for T575A in the first zinc finger of the DBD was markedly different

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 35

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations T575A, R629Q, and I672T alter the molecular function of the androgen receptor (AR), affecting its binding and transactivation capabilities, indicating a change in biochemical activity. Oncogenic: The passage mentions that the mutation K630 to glutamine increases transactivational activity and promotes prostate cancer cell survival and growth, suggesting that this variant contributes to tumor development or progression.

      Gene→Variant (gene-first): 2908:I672 2908:I672T 10499:R629 10499:R629Q 10499:T575A

      Genes: 2908 10499

      Variants: I672 I672T R629 R629Q T575A

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    6. karim2001khoury 19 Feb 2026
      The results for the AR NTD mutations investigated with PSA61Luc closely matched those for GRE2-TATA-Luc. AR mutation L57Q had loss of function at all concentrations of DHT with both reporters although they were less pron

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 34

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants L57Q, G142V, P390L, and P533S alter the function of the androgen receptor, indicating changes in activity in response to DHT, which aligns with evidence of altered molecular or biochemical function. Oncogenic: The variants are described in the context of their roles in tumor development or progression, particularly with references to gain or loss of function in the androgen receptor, which is relevant to cancer biology.

      Gene→Variant (gene-first): 2232:G142V 367:L57Q 367:P390L 367:P533S

      Genes: 2232 367

      Variants: G142V L57Q P390L P533S

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    7. karim2001khoury 19 Feb 2026
      In general, the profiles of PSA61Luc stimulation for the different AR mutations were very similar to those for GRE2-TATA-Luc; indicating that the findings in the broad GRE2-TATA-Luc study accurately reveal the effects of

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 33

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the AR mutations P390L, T575A, and R629Q affect the molecular function of the androgen receptor, specifically its affinity for regulatory elements, indicating a change in biochemical activity.

      Gene→Variant (gene-first): 367:P390L 10499:R629Q 10499:T575A

      Genes: 367 10499

      Variants: P390L R629Q T575A

      CIViC paragraph-level PMC3293822 Functional
    8. karim2001khoury 19 Feb 2026
      The LBD contained two mutations, D879G and Q919R, which fall within the grouping of loss to gain of function, although recovery to a modest 19% gain of function and WT levels respectively took place at only the highest c

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 30

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations D879G, H874Y, Q919R, and T877A alter the molecular or biochemical function of the protein, specifically in terms of gain or loss of function and ligand binding activity. Oncogenic: The mention of the mutated AR being expressed in a commonly used prostate cancer cell line (LNCaP) suggests that these mutations may contribute to tumor development or progression.

      Gene→Variant (gene-first): 10499:D879G 367:H874Y 367:Q919R 367:T877A

      Genes: 10499 367

      Variants: D879G H874Y Q919R T877A

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    9. karim2001khoury 19 Feb 2026
      Mutations K720E and R726L, which is implicated in a 6-fold increased risk of prostate cancer, reside in a positive cluster in helix 3 with lysine 720 creating a charged clamp with glutamate 897, and both residues partici

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 29

      Evidence Type(s): Predisposing, Functional

      Justification: Predisposing: The variant K720E is implicated in a 6-fold increased risk of prostate cancer, indicating its role in inherited risk for developing the disease. Functional: The passage discusses how mutations K720E and R726L impair binding of co-regulatory proteins and disrupt interactions, indicating that these variants alter molecular function. Additionally, N756's mutation to aspartate resulted in complete loss of function, further supporting its functional impact.

      Gene→Variant (gene-first): 367:A765T 9611:K720E 367:N756 367:Q902 367:Q902R 367:R726L 367:Y763C 9611:lysine 720

      Genes: 367 9611

      Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

      CIViC paragraph-level PMC3293822 Predisposing Functional
    10. karim2001khoury 19 Feb 2026
      Within the LBD, all but two loss of function mutations were clustered between residues 720 and 798. Of these, half had essentially no transactivational activity at physiological levels of DHT and comprise of L744F, A748V

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 28

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how specific mutations, including V757A and Q798E, show impaired binding to co-regulatory proteins and altered transactivational activity, indicating changes in molecular function. Oncogenic: The mention of loss of function mutations clustered in the ligand binding domain (LBD) and their association with reduced transactivational activity suggests a role in tumor development or progression, particularly in the context of antiandrogen treatment.

      Gene→Variant (gene-first): 367:A748V 367:A765T 9611:K720E 367:L744F 1387:M749 1387:M749I 9611:M886V 367:N756D 10514:Q798E 367:Q902R 367:R726L 367:S759P 10514:V757A 10514:V757I 367:Y763C

      Genes: 367 9611 1387 10514

      Variants: A748V A765T K720E L744F M749 M749I M886V N756D Q798E Q902R R726L S759P V757A V757I Y763C

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    11. karim2001khoury 19 Feb 2026
      Mutations in the LBD have historically been considered as the most likely candidates for driving PCa, therefore, the finding that the majority of mutations under investigation had no change from WT or loss of function wa

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 27

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the M886I mutation alters the interaction of the androgen receptor (AR) with co-activators and co-repressors, affecting transactivation ability, which indicates a change in molecular function. Oncogenic: The passage implies that the M886I mutation could significantly alter activity in prostate cancer, suggesting a role in tumor development or progression.

      Gene→Variant (gene-first): 367:K910R 9611:M886 9611:M886I

      Genes: 367 9611

      Variants: K910R M886 M886I

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    12. karim2001khoury 19 Feb 2026
      Within the hinge region, mutation I672T has been included in the arbitrary classification of no change from WT due to deviation of less than 10% at 0 and 0.1 nM DHT changing to a 14% gain of function at 10 nM. Interestin

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 25

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants A586V, A587S, T575A, R629Q, and I672T alter molecular function, specifically their effects on transactivational activity and ligand binding in response to different concentrations of DHT.

      Gene→Variant (gene-first): 597:A586V 367:A587S 2908:I672T 10499:R629Q 10499:T575A

      Genes: 597 367 2908 10499

      Variants: A586V A587S I672T R629Q T575A

      CIViC paragraph-level PMC3293822 Functional
    13. karim2001khoury 19 Feb 2026
      The only mutation to function like WT at low DHT and then gain function compared to WT upon DHT binding was P533S in the NTD. As with other groupings, mutations leading to constitutive transactivation activity were prese

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 23

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations (including P533S, G142V, M523V, G524D, and M537V) alter the transactivation activity of the androgen receptor, indicating that these variants affect molecular function related to protein activity in response to DHT. Oncogenic: The passage implies that the mutations contribute to prostate cancer by leading to constitutive transactivation activity, which is a characteristic of oncogenic variants that drive tumor development.

      Gene→Variant (gene-first): 2232:G142V 367:G524D 367:M523V 367:M537V 367:P533S

      Genes: 2232 367

      Variants: G142V G524D M523V M537V P533S

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    14. karim2001khoury 19 Feb 2026
      The novel class of mutation, namely loss of function at low levels or in the absence of DHT recovering to WT values or a gain of function upon binding of DHT was present in the NTD. Mutations P269S and S515G had WT level

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants P269S, P390L, P514S, and S515G alter transactivational activity in response to DHT, indicating a change in molecular function. Oncogenic: The mention of the variants impacting AR signaling suggests a role in tumor development or progression, as alterations in androgen receptor signaling are often associated with cancer.

      Gene→Variant (gene-first): 367:P269S 367:P390L 367:P514S 10514:S515G

      Genes: 367 10514

      Variants: P269S P390L P514S S515G

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    15. karim2001khoury 19 Feb 2026
      Interestingly, there was exiguous rescue at the highest concentration of DHT with D221H, P504L and D528G, while P340L manifested a striking dose-dependent recovery. The S296R mutation has been shown to have altered inter

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the S296R mutation alters interaction with the co-repressor N-CoR, causing reduced transactivational activity, and how the P340L mutation affects binding with TFIIF, indicating changes in molecular function. Oncogenic: The passage describes how the P340L mutation can drive prostate cancer progression through reduced growth suppression, indicating its role in tumor development.

      Gene→Variant (gene-first): 207:D221H 367:D528G 367:E198G 367:P269S 2232:P340L 9611:P504L 367:S296R 367:S334P

      Genes: 207 367 2232 9611

      Variants: D221H D528G E198G P269S P340L P504L S296R S334P

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    16. karim2001khoury 19 Feb 2026
      The predominant type of mutation i.e. loss of function, was well represented in the NTD. Mutations L57Q, E198G, D221H, A234T, S296R; S334P, P340L, P504L and D528G all displayed loss of function with E198G showing the gre

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations L57Q, E198G, D221H, A234T, S296R, S334P, P340L, P504L, and D528G result in loss of function, indicating that these variants alter molecular or biochemical function. Oncogenic: The mention of mutations leading to loss of function and their association with transactivational ability suggests a role in tumor development or progression, particularly in the context of the mutations being present in AIS (androgens insensitivity syndrome).

      Gene→Variant (gene-first): 1387:A234T 207:D221H 367:D528G 367:E198G 367:L57Q 2232:P340L 9611:P504L 367:S296R 367:S334P

      Genes: 1387 207 367 2232 9611

      Variants: A234T D221H D528G E198G L57Q P340L P504L S296R S334P

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    17. karim2001khoury 19 Feb 2026
      All five classes of mutation were represented within the NTD. Of the five mutations in AR classified as having no change from WT, G166S showed the least variance from the unmutated receptor. The mutation M537R also had m

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage indicates that the mutation M537R shows a 23% gain of function at a specific concentration of DHT, suggesting an alteration in molecular or biochemical function. Oncogenic: The mention of gain of function in a low androgen environment implies that the variant may contribute to tumor development or progression, characteristic of oncogenic behavior.

      Gene→Variant (gene-first): 367:G166S 367:M537R

      Genes: 367

      Variants: G166S M537R

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    18. karim2001khoury 19 Feb 2026
      Unsurprisingly, the DBD is virtually unaltered across a wide range of species with 100% homology between the examples shown here; except for two conservative substitutions in Xenopus, one of which T575, has been included

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the conservation and divergence of specific amino acids (T575, R629, I672) in relation to the function of the ligand-binding domain (LBD) of the androgen receptor, indicating that these variants may alter molecular function related to androgen binding.

      Gene→Variant (gene-first): 2908:I672 10499:R629 10499:T575

      Genes: 2908 10499

      Variants: I672 R629 T575

      CIViC paragraph-level PMC3293822 Functional
    19. karim2001khoury 19 Feb 2026
      The NTD is by far the least conserved domain with mouse, chicken and Xenopus having only 75, 32 and 34% similarity to human respectively. Alignment of the investigated human AR mutations to the primary sequence of AR in

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Functional

      Justification: Diagnostic: The passage discusses the conservation of mutated residues in the AR gene and their association with prostate cancer (PCa), indicating that these variants are used to classify or define a disease subtype. Functional: The passage mentions examining amino acids implicated in prostate cancer and suggests a possible role in the mechanics of AR function, indicating that these variants may alter molecular or biochemical function.

      Gene→Variant (gene-first): 1387:A234 207:D221 367:D528 367:E198 2232:G142 367:G166 367:G524 367:L57 367:M523 367:M537 367:P269 2232:P340 367:P390 367:P514 10514:P515 367:P533 367:S296 367:S334

      Genes: 1387 207 367 2232 10514

      Variants: A234 D221 D528 E198 G142 G166 G524 L57 M523 M537 P269 P340 P390 P514 P515 P533 S296 S334

      CIViC paragraph-level PMC3293822 Diagnostic Functional
    20. karim2001khoury 19 Feb 2026
      This analysis examined 45 single missense mutations detected in PCa with metastasis or high Gleason scores, and which extend along the entire length of the protein. Our sensitive assay system uncovered a previously unide

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 43

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how specific mutations (e.g., G142V, M523V, G524D, M537V) alter transactivational activity and regulatory element binding, indicating changes in molecular function. Oncogenic: The analysis of mutations in the context of prostate cancer (PCa) suggests that these variants contribute to tumor development or progression, particularly through their effects on transactivational activity related to cancer-related genes.

      Gene→Variant (gene-first): 2232:G142V 367:G524D 367:M523V 367:M537V 1387:M749I 10514:Q798E 10499:R629Q 10499:T575A

      Genes: 2232 367 1387 10514 10499

      Variants: G142V G524D M523V M537V M749I Q798E R629Q T575A

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    21. karim2001khoury 19 Feb 2026
      Mutations with no apparent change of activity from WT may be able to drive cancer progression though several diverse routes. These include altered binding to co-repressors or co-regulators e.g. M886I, regulatory element-

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 41

      Evidence Type(s): Oncogenic, Functional

      Justification: Oncogenic: The passage discusses how the M886I variant may drive cancer progression through altered binding and other mechanisms, indicating its role in tumor development. Functional: The passage mentions that the M886I variant may alter binding to co-repressors or co-regulators, which suggests a change in molecular function.

      Gene→Variant (gene-first): 9611:M886I

      Genes: 9611

      Variants: M886I

      CIViC paragraph-level PMC3293822 Oncogenic Functional
    22. karim2001khoury 19 Feb 2026
      The LBD mutations had a greater dependence on the regulatory elements, emphasizing the importance of interdomain communication for receptor function. While the major losses of function seen with M749I at 10 nM DHT were c

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 36

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants M749I, Q798E, and H874Y alter the molecular function of the androgen receptor, specifically in terms of their constitutive activity and loss of function in response to DHT. Oncogenic: The passage indicates that the mutations M749I, Q798E, and H874Y may contribute to prostate cancer development and progression, particularly through their effects on androgen receptor signaling and activity.

      Gene→Variant (gene-first): 367:H874Y 1387:M749I 10514:Q798E

      Genes: 367 1387 10514

      Variants: H874Y M749I Q798E

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    23. karim2001khoury 19 Feb 2026
      Mutations within the DBD and hinge domains of the AR would be expected to have the greatest influence on regulating ARE binding and indeed, the profile for T575A in the first zinc finger of the DBD was markedly different

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 35

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations T575A, R629Q, and I672T alter the molecular function of the androgen receptor (AR), affecting its binding and transactivation capabilities, indicating a change in biochemical activity. Oncogenic: The passage mentions that the mutation K630 to glutamine increases transactivational activity and promotes prostate cancer cell survival and growth, suggesting that this variant contributes to tumor development or progression.

      Gene→Variant (gene-first): 2908:I672 2908:I672T 10499:R629 10499:R629Q 10499:T575A

      Genes: 2908 10499

      Variants: I672 I672T R629 R629Q T575A

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    24. karim2001khoury 19 Feb 2026
      The results for the AR NTD mutations investigated with PSA61Luc closely matched those for GRE2-TATA-Luc. AR mutation L57Q had loss of function at all concentrations of DHT with both reporters although they were less pron

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 34

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants L57Q, G142V, P390L, and P533S alter the function of the androgen receptor, indicating changes in activity in response to DHT, which aligns with evidence of altered molecular or biochemical function. Oncogenic: The variants are described in the context of their roles in tumor development or progression, particularly with references to gain or loss of function in the androgen receptor, which is relevant to cancer biology.

      Gene→Variant (gene-first): 2232:G142V 367:L57Q 367:P390L 367:P533S

      Genes: 2232 367

      Variants: G142V L57Q P390L P533S

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    25. karim2001khoury 19 Feb 2026
      In general, the profiles of PSA61Luc stimulation for the different AR mutations were very similar to those for GRE2-TATA-Luc; indicating that the findings in the broad GRE2-TATA-Luc study accurately reveal the effects of

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 33

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the AR mutations P390L, T575A, and R629Q affect the molecular function of the androgen receptor, specifically its affinity for regulatory elements, indicating a change in biochemical activity.

      Gene→Variant (gene-first): 367:P390L 10499:R629Q 10499:T575A

      Genes: 367 10499

      Variants: P390L R629Q T575A

      CIViC paragraph-level PMC3293822 Functional
    26. karim2001khoury 19 Feb 2026
      The LBD contained two mutations, D879G and Q919R, which fall within the grouping of loss to gain of function, although recovery to a modest 19% gain of function and WT levels respectively took place at only the highest c

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 30

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations D879G, H874Y, Q919R, and T877A alter the molecular or biochemical function of the protein, specifically in terms of gain or loss of function and ligand binding activity. Oncogenic: The mention of the mutated AR being expressed in a commonly used prostate cancer cell line (LNCaP) suggests that these mutations may contribute to tumor development or progression.

      Gene→Variant (gene-first): 10499:D879G 367:H874Y 367:Q919R 367:T877A

      Genes: 10499 367

      Variants: D879G H874Y Q919R T877A

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    27. karim2001khoury 19 Feb 2026
      Mutations K720E and R726L, which is implicated in a 6-fold increased risk of prostate cancer, reside in a positive cluster in helix 3 with lysine 720 creating a charged clamp with glutamate 897, and both residues partici

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 29

      Evidence Type(s): Predisposing, Functional

      Justification: Predisposing: The variant K720E is implicated in a 6-fold increased risk of prostate cancer, indicating its role in inherited risk for developing the disease. Functional: The passage discusses how mutations K720E and R726L impair binding of co-regulatory proteins and disrupt interactions, indicating that these variants alter molecular function. Additionally, N756's mutation to aspartate resulted in complete loss of function, further supporting its functional impact.

      Gene→Variant (gene-first): 367:A765T 9611:K720E 367:N756 367:Q902 367:Q902R 367:R726L 367:Y763C 9611:lysine 720

      Genes: 367 9611

      Variants: A765T K720E N756 Q902 Q902R R726L Y763C lysine 720

      CIViC paragraph-level PMC3293822 Predisposing Functional
    28. karim2001khoury 19 Feb 2026
      Within the LBD, all but two loss of function mutations were clustered between residues 720 and 798. Of these, half had essentially no transactivational activity at physiological levels of DHT and comprise of L744F, A748V

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 28

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how specific mutations, including V757A and Q798E, show impaired binding to co-regulatory proteins and altered transactivational activity, indicating changes in molecular function. Oncogenic: The mention of loss of function mutations clustered in the ligand binding domain (LBD) and their association with reduced transactivational activity suggests a role in tumor development or progression, particularly in the context of antiandrogen treatment.

      Gene→Variant (gene-first): 367:A748V 367:A765T 9611:K720E 367:L744F 1387:M749 1387:M749I 9611:M886V 367:N756D 10514:Q798E 367:Q902R 367:R726L 367:S759P 10514:V757A 10514:V757I 367:Y763C

      Genes: 367 9611 1387 10514

      Variants: A748V A765T K720E L744F M749 M749I M886V N756D Q798E Q902R R726L S759P V757A V757I Y763C

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    29. karim2001khoury 19 Feb 2026
      Mutations in the LBD have historically been considered as the most likely candidates for driving PCa, therefore, the finding that the majority of mutations under investigation had no change from WT or loss of function wa

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 27

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the M886I mutation alters the interaction of the androgen receptor (AR) with co-activators and co-repressors, affecting transactivation ability, which indicates a change in molecular function. Oncogenic: The passage implies that the M886I mutation could significantly alter activity in prostate cancer, suggesting a role in tumor development or progression.

      Gene→Variant (gene-first): 367:K910R 9611:M886 9611:M886I

      Genes: 367 9611

      Variants: K910R M886 M886I

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    30. karim2001khoury 19 Feb 2026
      Within the hinge region, mutation I672T has been included in the arbitrary classification of no change from WT due to deviation of less than 10% at 0 and 0.1 nM DHT changing to a 14% gain of function at 10 nM. Interestin

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 25

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the variants A586V, A587S, T575A, R629Q, and I672T alter molecular function, specifically their effects on transactivational activity and ligand binding in response to different concentrations of DHT.

      Gene→Variant (gene-first): 597:A586V 367:A587S 2908:I672T 10499:R629Q 10499:T575A

      Genes: 597 367 2908 10499

      Variants: A586V A587S I672T R629Q T575A

      CIViC paragraph-level PMC3293822 Functional
    31. karim2001khoury 19 Feb 2026
      The only mutation to function like WT at low DHT and then gain function compared to WT upon DHT binding was P533S in the NTD. As with other groupings, mutations leading to constitutive transactivation activity were prese

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 23

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations (including P533S, G142V, M523V, G524D, and M537V) alter the transactivation activity of the androgen receptor, indicating that these variants affect molecular function related to protein activity in response to DHT. Oncogenic: The passage implies that the mutations contribute to prostate cancer by leading to constitutive transactivation activity, which is a characteristic of oncogenic variants that drive tumor development.

      Gene→Variant (gene-first): 2232:G142V 367:G524D 367:M523V 367:M537V 367:P533S

      Genes: 2232 367

      Variants: G142V G524D M523V M537V P533S

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    32. karim2001khoury 19 Feb 2026
      The novel class of mutation, namely loss of function at low levels or in the absence of DHT recovering to WT values or a gain of function upon binding of DHT was present in the NTD. Mutations P269S and S515G had WT level

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 22

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the variants P269S, P390L, P514S, and S515G alter transactivational activity in response to DHT, indicating a change in molecular function. Oncogenic: The mention of the variants impacting AR signaling suggests a role in tumor development or progression, as alterations in androgen receptor signaling are often associated with cancer.

      Gene→Variant (gene-first): 367:P269S 367:P390L 367:P514S 10514:S515G

      Genes: 367 10514

      Variants: P269S P390L P514S S515G

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    33. karim2001khoury 19 Feb 2026
      Interestingly, there was exiguous rescue at the highest concentration of DHT with D221H, P504L and D528G, while P340L manifested a striking dose-dependent recovery. The S296R mutation has been shown to have altered inter

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 21

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the S296R mutation alters interaction with the co-repressor N-CoR, causing reduced transactivational activity, and how the P340L mutation affects binding with TFIIF, indicating changes in molecular function. Oncogenic: The passage describes how the P340L mutation can drive prostate cancer progression through reduced growth suppression, indicating its role in tumor development.

      Gene→Variant (gene-first): 207:D221H 367:D528G 367:E198G 367:P269S 2232:P340L 9611:P504L 367:S296R 367:S334P

      Genes: 207 367 2232 9611

      Variants: D221H D528G E198G P269S P340L P504L S296R S334P

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    34. karim2001khoury 19 Feb 2026
      The predominant type of mutation i.e. loss of function, was well represented in the NTD. Mutations L57Q, E198G, D221H, A234T, S296R; S334P, P340L, P504L and D528G all displayed loss of function with E198G showing the gre

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 20

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the mutations L57Q, E198G, D221H, A234T, S296R, S334P, P340L, P504L, and D528G result in loss of function, indicating that these variants alter molecular or biochemical function. Oncogenic: The mention of mutations leading to loss of function and their association with transactivational ability suggests a role in tumor development or progression, particularly in the context of the mutations being present in AIS (androgens insensitivity syndrome).

      Gene→Variant (gene-first): 1387:A234T 207:D221H 367:D528G 367:E198G 367:L57Q 2232:P340L 9611:P504L 367:S296R 367:S334P

      Genes: 1387 207 367 2232 9611

      Variants: A234T D221H D528G E198G L57Q P340L P504L S296R S334P

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    35. karim2001khoury 19 Feb 2026
      All five classes of mutation were represented within the NTD. Of the five mutations in AR classified as having no change from WT, G166S showed the least variance from the unmutated receptor. The mutation M537R also had m

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 19

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage indicates that the mutation M537R shows a 23% gain of function at a specific concentration of DHT, suggesting an alteration in molecular or biochemical function. Oncogenic: The mention of gain of function in a low androgen environment implies that the variant may contribute to tumor development or progression, characteristic of oncogenic behavior.

      Gene→Variant (gene-first): 367:G166S 367:M537R

      Genes: 367

      Variants: G166S M537R

      CIViC paragraph-level PMC3293822 Functional Oncogenic
    36. karim2001khoury 19 Feb 2026
      Unsurprisingly, the DBD is virtually unaltered across a wide range of species with 100% homology between the examples shown here; except for two conservative substitutions in Xenopus, one of which T575, has been included

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses the conservation and divergence of specific amino acids (T575, R629, I672) in relation to the function of the ligand-binding domain (LBD) of the androgen receptor, indicating that these variants may alter molecular function related to androgen binding.

      Gene→Variant (gene-first): 2908:I672 10499:R629 10499:T575

      Genes: 2908 10499

      Variants: I672 R629 T575

      CIViC paragraph-level PMC3293822 Functional
    37. karim2001khoury 19 Feb 2026
      The NTD is by far the least conserved domain with mouse, chicken and Xenopus having only 75, 32 and 34% similarity to human respectively. Alignment of the investigated human AR mutations to the primary sequence of AR in

      [Paragraph-level] PMCID: PMC3293822 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Diagnostic, Functional

      Justification: Diagnostic: The passage discusses the conservation of mutated residues in the AR gene and their association with prostate cancer (PCa), indicating that these variants are used to classify or define a disease subtype. Functional: The passage mentions examining amino acids implicated in prostate cancer and suggests a possible role in the mechanics of AR function, indicating that these variants may alter molecular or biochemical function.

      Gene→Variant (gene-first): 1387:A234 207:D221 367:D528 367:E198 2232:G142 367:G166 367:G524 367:L57 367:M523 367:M537 367:P269 2232:P340 367:P390 367:P514 10514:P515 367:P533 367:S296 367:S334

      Genes: 1387 207 367 2232 10514

      Variants: A234 D221 D528 E198 G142 G166 G524 L57 M523 M537 P269 P340 P390 P514 P515 P533 S296 S334

      CIViC paragraph-level PMC3293822 Diagnostic Functional
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    pmc.ncbi.nlm.nih.gov/articles/PMC3293822/pdf/pone.0032514.pdf