[Paper-level Aggregated] PMCID: PMC5019182

Evidence Type(s): Functional

Summary: Mutation: p.Ala1035Thr | Summary: The p.Ala1035Thr mutation has been demonstrated to alter molecular function through a gain-of-function mechanism.

Evidence Type: Functional Mutation: p.Ala1035Val | Summary: The p.Ala1035Val mutation has been demonstrated to alter molecular function through a gain-of-function mechanism.

Gene→Variant (gene-first): PIK3CA(5290):p.Ala1035Thr PIK3CA(5290):p.Ala1035Val

Genes: PIK3CA(5290)

Variants: p.Ala1035Thr p.Ala1035Val

[Paper-level Aggregated] PMCID: PMC5019182

Evidence Type(s): Oncogenic

Summary: Mutation: p.Glu545Lys | Summary: The p.Glu545Lys mutation is identified as an oncogenic mutation contributing to tumor development or progression, associated with a gain-of-function mechanism and noted as a hotspot mutation in cancer, as indicated by its presence in the Catalogue of Somatic Mutations in Cancer (COSMIC).

Evidence Type: Oncogenic Mutation: p.His1047Arg | Summary: The p.His1047Arg mutation is classified as an oncogenic mutation, described as a low-level mosaic variant associated with features of CLOVES syndrome, contributing to tumor development or progression, supported by its identification in the Catalogue of Somatic Mutations in Cancer (COSMIC).

Evidence Type: Oncogenic Mutation: p.Arg93Gln | Summary: The p.Arg93Gln mutation was identified in patients with features overlapping MCAP and is associated with tumor development or progression, indicating its potential role as a somatic variant contributing to cancer.

Evidence Type: Oncogenic Mutation: p.Asn345Thr | Summary: The p.Asn345Thr mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Glu545Asp | Summary: The p.Glu545Asp mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Gln546His | Summary: The p.Gln546His mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Asn345Lys | Summary: The p.Asn345Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Glu545Gly | Summary: The p.Glu545Gly mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Gln546Lys | Summary: The p.Gln546Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Gln546Pro | Summary: The p.Gln546Pro mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Tyr1021His | Summary: The p.Tyr1021His mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Evidence Type: Oncogenic Mutation: p.Glu726Lys | Summary: The p.Glu726Lys mutation in PIK3CA is implicated in tumor development and progression, contributing to the oncogenic characteristics observed in patients with MCAP.

Evidence Type: Oncogenic Mutation: p.Gly106Val | Summary: The p.Gly106Val mutation was found in a patient with congenital onset somatic overgrowth and other features, indicating its potential contribution to tumor development or progression.

Evidence Type: Oncogenic Mutation: p.Cys378Tyr | Summary: The p.Cys378Tyr mutation was described as a mosaic variant in a patient with hemihypertrophy and capillary malformations, suggesting its involvement in tumor development or progression.

Evidence Type: Oncogenic Mutation: p.Glu453Lys | Summary: The p.Glu453Lys mutation is associated with various congenital overgrowth syndromes, indicating its role in tumor development or progression in affected tissues.

Evidence Type: Oncogenic Mutation: p.Gly914Arg | Summary: The p.Gly914Arg mutation is linked to congenital overgrowth conditions, suggesting its contribution to tumor development or progression in affected individuals.

Evidence Type: Oncogenic Mutation: p.Glu542Lys | Summary: The p.Glu542Lys mutation is identified as a hotspot mutation commonly seen in cancer, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): PIK3CA(5290):p.Glu545Lys PIK3CA(5290):p.His1047Arg PIK3CA(5290):p.Arg93Gln PIK3CA(5290):p.Asn345Thr PIK3CA(5290):p.Glu545Asp PIK3CA(5290):p.Gln546His PIK3CA(5290):p.Asn345Lys PIK3CA(5290):p.Glu545Gly PIK3CA(5290):p.Gln546Lys PIK3CA(5290):p.Gln546Pro TSC2(7249):p.Tyr1021His PIK3CA(5290):p.Glu726Lys PIK3CA(5290):p.Gly106Val PIK3CA(5290):p.Cys378Tyr PIK3CA(5290):p.Glu453Lys PIK3CA(5290):p.Gly914Arg PIK3CA(5290):p.Glu542Lys

Genes: PIK3CA(5290) TSC2(7249)

Variants: p.Glu545Lys p.His1047Arg p.Arg93Gln p.Asn345Thr p.Glu545Asp p.Gln546His p.Asn345Lys p.Glu545Gly p.Gln546Lys p.Gln546Pro p.Tyr1021His p.Glu726Lys p.Gly106Val p.Cys378Tyr p.Glu453Lys p.Gly914Arg p.Glu542Lys

[Paper-level Aggregated] PMCID: PMC5019182

Evidence Type(s): Predisposing

Summary: Mutation: p.Glu726Lys | Summary: The presence of the p.Glu726Lys mutation in patients indicates a potential inherited risk for developing MCAP and its associated features.

Gene→Variant (gene-first): PIK3CA(5290):p.Glu726Lys

Genes: PIK3CA(5290)

Variants: p.Glu726Lys

[Paper-level Aggregated] PMCID: PMC5019182

Evidence Type(s): Diagnostic

Summary: Mutation: p.Glu542Lys | Summary: The p.Glu542Lys mutation is associated with developmental pediatric disorders, indicating its role in defining or classifying a disease subtype.

Evidence Type: Diagnostic Mutation: p.Glu545Lys | Summary: The p.Glu545Lys mutation is frequently observed in pediatric disorders, supporting its use in defining or classifying a disease subtype.

Evidence Type: Diagnostic Mutation: p.His1047Arg | Summary: The p.His1047Arg mutation is highly recurrent in developmental pediatric disorders, suggesting its role in defining or classifying a disease subtype.

Evidence Type: Diagnostic Mutation: p.Glu726Lys | Summary: The p.Glu726Lys mutation is associated with classic features of MCAP, which helps in defining and classifying the disease.

Gene→Variant (gene-first): PIK3CA(5290):p.Glu542Lys PIK3CA(5290):p.Glu545Lys PIK3CA(5290):p.His1047Arg PIK3CA(5290):p.Glu726Lys

Genes: PIK3CA(5290)

Variants: p.Glu542Lys p.Glu545Lys p.His1047Arg p.Glu726Lys

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 19

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.Glu542Lys | Summary: The p.Glu542Lys mutation is identified as a hotspot mutation commonly seen in cancer, indicating its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: p.Glu545Lys | Summary: The p.Glu545Lys mutation is also noted as a hotspot mutation in cancer, suggesting its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: p.His1047Arg | Summary: The p.His1047Arg mutation is described as a low-level mosaic variant, which is associated with features of CLOVES syndrome, indicating its potential contribution to tumor development or progression.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.Glu453Lys | Summary: The p.Glu453Lys mutation is associated with various congenital overgrowth syndromes, indicating its role in tumor development or progression in affected tissues. Evidence Type: Oncogenic | Mutation: p.Gly914Arg | Summary: The p.Gly914Arg mutation is linked to congenital overgrowth conditions, suggesting its contribution to tumor development or progression in affected individuals.

Gene→Variant (gene-first): 5290:p.Glu453Lys 5290:p.Gly914Arg

Genes: 5290

Variants: p.Glu453Lys p.Gly914Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 16

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.Arg93Gln | Summary: The p.Arg93Gln mutation was identified in patients with features overlapping MCAP, suggesting its role in tumor development or progression, particularly as it was present in a significant percentage of alleles in peripheral blood lymphocytes. Evidence Type: Oncogenic | Mutation: p.Gly106Val | Summary: The p.Gly106Val mutation was found in a patient with congenital onset somatic overgrowth and other features, indicating its potential contribution to tumor development or progression, as it was present in a notable percentage of alleles in blood and skin. Evidence Type: Oncogenic | Mutation: p.Cys378Tyr | Summary: The p.Cys378Tyr mutation was described as a mosaic variant in a patient with hemihypertrophy and capillary malformations, suggesting its involvement in tumor development or progression, given its presence in a percentage of alleles in blood-derived DNA.

Gene→Variant (gene-first): 5290:p.Arg93Gln 5290:p.Cys378Tyr 5290:p.Gly106Val

Genes: 5290

Variants: p.Arg93Gln p.Cys378Tyr p.Gly106Val

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Summary: Evidence Type: Diagnostic | Mutation: p.Glu726Lys | Summary: The p.Glu726Lys mutation is associated with classic features of MCAP, which helps in defining and classifying the disease. Evidence Type: Predisposing | Mutation: p.Glu726Lys | Summary: The presence of the p.Glu726Lys mutation in patients indicates a potential inherited risk for developing MCAP and its associated features. Evidence Type: Oncogenic | Mutation: p.Glu726Lys | Summary: The p.Glu726Lys mutation in PIK3CA is implicated in tumor development and progression, contributing to the oncogenic characteristics observed in patients with MCAP.

Gene→Variant (gene-first): 5290:p.Glu726Lys

Genes: 5290

Variants: p.Glu726Lys

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.Asn345Thr | Summary: The p.Asn345Thr mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Glu545Asp | Summary: The p.Glu545Asp mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Gln546His | Summary: The p.Gln546His mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Asn345Lys | Summary: The p.Asn345Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Glu545Lys | Summary: The p.Glu545Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Glu545Gly | Summary: The p.Glu545Gly mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Gln546Lys | Summary: The p.Gln546Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Gln546Pro | Summary: The p.Gln546Pro mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: p.Tyr1021His | Summary: The p.Tyr1021His mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Functional | Mutation: p.Ala1035Thr | Summary: The p.Ala1035Thr mutation has been demonstrated to alter molecular function through a gain-of-function mechanism. Evidence Type: Functional | Mutation: p.Ala1035Val | Summary: The p.Ala1035Val mutation has been demonstrated to alter molecular function through a gain-of-function mechanism. Evidence Type: Oncogenic | Mutation: Glu545Ala | Summary: The Glu545Ala mutation is associated with a gain-of-function mechanism and contributes to tumor development. Evidence Type: Oncogenic | Mutation: Glu545Lys | Summary: The Glu545Lys mutation is associated with a gain-of-function mechanism and contributes to tumor development.

Gene→Variant (gene-first): 5290:Glu545Ala 5290:Glu545Lys 5290:p.Ala1035Thr 5290:p.Ala1035Val 5290:p.Asn345Lys 5290:p.Asn345Thr 5290:p.Gln546His 5290:p.Gln546Lys 5290:p.Gln546Pro 5290:p.Glu545Asp 5290:p.Glu545Gly 5290:p.Glu545Lys 5290:p.Tyr1021Cys 7249:p.Tyr1021His

Genes: 5290 7249

Variants: Glu545Ala Glu545Lys p.Ala1035Thr p.Ala1035Val p.Asn345Lys p.Asn345Thr p.Gln546His p.Gln546Lys p.Gln546Pro p.Glu545Asp p.Glu545Gly p.Glu545Lys p.Tyr1021Cys p.Tyr1021His

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic

Summary: Evidence Type: Diagnostic | Mutation: p.Glu542Lys | Summary: The p.Glu542Lys mutation is associated with developmental pediatric disorders, indicating its role in defining or classifying a disease subtype. Evidence Type: Diagnostic | Mutation: p.Glu545Lys | Summary: The p.Glu545Lys mutation is frequently observed in pediatric disorders, supporting its use in defining or classifying a disease subtype. Evidence Type: Diagnostic | Mutation: p.His1047Arg | Summary: The p.His1047Arg mutation is highly recurrent in developmental pediatric disorders, suggesting its role in defining or classifying a disease subtype.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.Glu726Lys 5290:p.Gly914Arg 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.Glu726Lys p.Gly914Arg p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.Arg93Gln | Summary: The p.Arg93Gln mutation was identified in a patient and is associated with tumor development or progression, indicating its potential role as a somatic variant contributing to cancer.

Gene→Variant (gene-first): 5290:p.Arg93Gln

Genes: 5290

Variants: p.Arg93Gln

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.Glu545Lys | Summary: The p.Glu545Lys mutation is identified as an oncogenic mutation contributing to tumor development or progression, as indicated by its presence in the Catalogue of Somatic Mutations in Cancer (COSMIC). Evidence Type: Oncogenic | Mutation: p.His1047Arg | Summary: The p.His1047Arg mutation is also classified as an oncogenic mutation, contributing to tumor development or progression, supported by its identification in the Catalogue of Somatic Mutations in Cancer (COSMIC).

Gene→Variant (gene-first): 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu545Lys p.His1047Arg

[Paper-level Aggregated] PMCID: PMC5019182

Evidence Type(s): Oncogenic, Functional, Predisposing, Diagnostic, Prognostic

Justification: Oncogenic: The text states that all identified mutations in PIK3CA, including p.Glu545Lys and p.His1047Arg, are oncogenic and have been documented in the Catalogue of Somatic Mutations in Cancer (COSMIC). Functional: The passage mentions that most mutations are proven or predicted to have a gain-of-function (GOF) mechanism, with published functional studies demonstrating GOF for at least 9 of the 41 mutations identified. Predisposing: The text describes that several patients with PIK3CA mutations exhibit classic features of MCAP and other developmental disorders, indicating that these mutations predispose individuals to these conditions. Diagnostic: The identification of PIK3CA mutations through clinical testing methods such as targeted NGS and whole-exome sequencing suggests that these mutations can serve as diagnostic markers for related developmental disorders. Prognostic: The presence of specific mutations and their associated alternative allele percentages (AAPs) in patients may provide insights into the clinical outcomes and severity of the associated phenotypes, indicating a prognostic value.

Gene→Variant (gene-first): PIK3CA(5290):Glu545Ala PIK3CA(5290):Glu545Lys PIK3CA(5290):p.Ala1035Thr PIK3CA(5290):p.Ala1035Val PIK3CA(5290):p.Asn345Lys PIK3CA(5290):p.Asn345Thr PIK3CA(5290):p.Gln546His PIK3CA(5290):p.Gln546Lys PIK3CA(5290):p.Gln546Pro PIK3CA(5290):p.Glu545Asp PIK3CA(5290):p.Glu545Gly PIK3CA(5290):p.Glu545Lys PIK3CA(5290):p.Tyr1021Cys TSC2(7249):p.Tyr1021His PIK3CA(5290):p.Arg93Gln PIK3CA(5290):p.Cys378Tyr PIK3CA(5290):p.Gly106Val PIK3CA(5290):p.Glu453Lys PIK3CA(5290):p.Gly914Arg PIK3CA(5290):p.Glu542Lys PIK3CA(5290):p.Glu726Lys PIK3CA(5290):p.His1047Arg

Genes: PIK3CA(5290) TSC2(7249)

Variants: Glu545Ala Glu545Lys p.Ala1035Thr p.Ala1035Val p.Asn345Lys p.Asn345Thr p.Gln546His p.Gln546Lys p.Gln546Pro p.Glu545Asp p.Glu545Gly p.Glu545Lys p.Tyr1021Cys p.Tyr1021His p.Arg93Gln p.Cys378Tyr p.Gly106Val p.Glu453Lys p.Gly914Arg p.Glu542Lys p.Glu726Lys p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 19

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of specific PIK3CA mutations in patients with distinct clinical features, indicating that these mutations are associated with certain syndromes, such as linear nevus sebaceous or Schimmelpenning syndrome and CLOVES syndrome. Oncogenic: The passage mentions that the PIK3CA mutations are "hotspot" mutations commonly seen in cancer, suggesting that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 17

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of the p.Glu453Lys and p.Gly914Arg mutations in patients with specific congenital conditions, indicating their association with the phenotypes observed, which supports their use in defining or classifying the disease. Oncogenic: The p.Glu453Lys and p.Gly914Arg mutations are described in the context of patients with congenital overgrowth syndromes, suggesting a role in tumor development or progression, particularly in the context of somatic mutations.

Gene→Variant (gene-first): 5290:p.Glu453Lys 5290:p.Gly914Arg

Genes: 5290

Variants: p.Glu453Lys p.Gly914Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 16

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of specific mutations (p.Arg93Gln, p.Gly106Val, p.Cys378Tyr) in patients with phenotypes that overlap with or suggest variants of MCAP, indicating that these mutations are associated with defining or classifying the disease. Oncogenic: The passage describes the mutations as somatic variants present in patients with specific phenotypes, suggesting their contribution to tumor development or progression, particularly in the context of the patients' conditions.

Gene→Variant (gene-first): 5290:p.Arg93Gln 5290:p.Cys378Tyr 5290:p.Gly106Val

Genes: 5290

Variants: p.Arg93Gln p.Cys378Tyr p.Gly106Val

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses individuals with mosaic PIK3CA mutations, including the p.Glu726Lys variant, in the context of classic features of MCAP, indicating its role in defining or classifying the disease. Predisposing: The passage mentions that several patients with the p.Glu726Lys mutation had various clinical findings associated with MCAP, suggesting an inherited risk for developing this condition.

Gene→Variant (gene-first): 5290:p.Glu726Lys

Genes: 5290

Variants: p.Glu726Lys

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses mutations that are proven or predicted to have a gain-of-function mechanism, indicating that these somatic variants contribute to tumor development or progression. Diagnostic: The mention of Glu545Ala and Glu545Lys mutations being detected in individuals with undefined "Cowden-like" features suggests an association with a specific disease or phenotype, supporting their use in diagnosis.

Gene→Variant (gene-first): 5290:Glu545Ala 5290:Glu545Lys 5290:p.Ala1035Thr 5290:p.Ala1035Val 5290:p.Asn345Lys 5290:p.Asn345Thr 5290:p.Gln546His 5290:p.Gln546Lys 5290:p.Gln546Pro 5290:p.Glu545Asp 5290:p.Glu545Gly 5290:p.Glu545Lys 5290:p.Tyr1021Cys 7249:p.Tyr1021His

Genes: 5290 7249

Variants: Glu545Ala Glu545Lys p.Ala1035Thr p.Ala1035Val p.Asn345Lys p.Asn345Thr p.Gln546His p.Gln546Lys p.Gln546Pro p.Glu545Asp p.Glu545Gly p.Glu545Lys p.Tyr1021Cys p.Tyr1021His

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of PIK3CA mutations with developmental pediatric disorders, indicating that these mutations are used to classify or define the disease phenotypes. Oncogenic: The mention of PIK3CA mutations, particularly the hotspot mutations, suggests their role in tumor development or progression, as they are frequently observed in affected individuals.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.Glu726Lys 5290:p.Gly914Arg 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.Glu726Lys p.Gly914Arg p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 8

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage discusses the identification of mutations in patients, including the p.Arg93Gln variant, suggesting its association with specific cases and indicating its role in defining or confirming a disease.

Gene→Variant (gene-first): 5290:p.Arg93Gln

Genes: 5290

Variants: p.Arg93Gln

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses mutations of PIK3CA, including p.Glu545Lys and p.His1047Arg, which are identified as oncogenic mutations contributing to tumor development or progression, as indicated by their presence in the Catalogue of Somatic Mutations in Cancer (COSMIC). Functional: The passage mentions the alternative allele percentages (AAP) of the mutations, indicating that these variants may alter molecular or biochemical function, as evidenced by the variation in AAPs across different sample types.

Gene→Variant (gene-first): 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu545Lys p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 19

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of specific PIK3CA mutations in patients with distinct clinical features, indicating that these mutations are associated with certain syndromes, such as linear nevus sebaceous or Schimmelpenning syndrome and CLOVES syndrome. Oncogenic: The passage mentions that the PIK3CA mutations are "hotspot" mutations commonly seen in cancer, suggesting that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 17

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of the p.Glu453Lys and p.Gly914Arg mutations in patients with specific congenital conditions, indicating their association with the phenotypes observed, which supports their use in defining or classifying the disease. Oncogenic: The p.Glu453Lys and p.Gly914Arg mutations are described in the context of patients with congenital overgrowth syndromes, suggesting a role in tumor development or progression, particularly in the context of somatic mutations.

Gene→Variant (gene-first): 5290:p.Glu453Lys 5290:p.Gly914Arg

Genes: 5290

Variants: p.Glu453Lys p.Gly914Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 16

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of specific mutations (p.Arg93Gln, p.Gly106Val, p.Cys378Tyr) in patients with phenotypes that overlap with or suggest variants of MCAP, indicating that these mutations are associated with defining or classifying the disease. Oncogenic: The passage describes the mutations as somatic variants present in patients with specific phenotypes, suggesting their contribution to tumor development or progression, particularly in the context of the patients' conditions.

Gene→Variant (gene-first): 5290:p.Arg93Gln 5290:p.Cys378Tyr 5290:p.Gly106Val

Genes: 5290

Variants: p.Arg93Gln p.Cys378Tyr p.Gly106Val

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage discusses individuals with mosaic PIK3CA mutations, including the p.Glu726Lys variant, in the context of classic features of MCAP, indicating its role in defining or classifying the disease. Predisposing: The passage mentions that several patients with the p.Glu726Lys mutation had various clinical findings associated with MCAP, suggesting an inherited risk for developing this condition.

Gene→Variant (gene-first): 5290:p.Glu726Lys

Genes: 5290

Variants: p.Glu726Lys

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses mutations that are proven or predicted to have a gain-of-function mechanism, indicating that these somatic variants contribute to tumor development or progression. Diagnostic: The mention of Glu545Ala and Glu545Lys mutations being detected in individuals with undefined "Cowden-like" features suggests an association with a specific disease or phenotype, supporting their use in diagnosis.

Gene→Variant (gene-first): 5290:Glu545Ala 5290:Glu545Lys 5290:p.Ala1035Thr 5290:p.Ala1035Val 5290:p.Asn345Lys 5290:p.Asn345Thr 5290:p.Gln546His 5290:p.Gln546Lys 5290:p.Gln546Pro 5290:p.Glu545Asp 5290:p.Glu545Gly 5290:p.Glu545Lys 5290:p.Tyr1021Cys 7249:p.Tyr1021His

Genes: 5290 7249

Variants: Glu545Ala Glu545Lys p.Ala1035Thr p.Ala1035Val p.Asn345Lys p.Asn345Thr p.Gln546His p.Gln546Lys p.Gln546Pro p.Glu545Asp p.Glu545Gly p.Glu545Lys p.Tyr1021Cys p.Tyr1021His

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of PIK3CA mutations with developmental pediatric disorders, indicating that these mutations are used to classify or define the disease phenotypes. Oncogenic: The mention of PIK3CA mutations, particularly the hotspot mutations, suggests their role in tumor development or progression, as they are frequently observed in affected individuals.

Gene→Variant (gene-first): 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.Glu726Lys 5290:p.Gly914Arg 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu542Lys p.Glu545Lys p.Glu726Lys p.Gly914Arg p.His1047Arg

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 8

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage discusses the identification of mutations in patients, including the p.Arg93Gln variant, suggesting its association with specific cases and indicating its role in defining or confirming a disease.

Gene→Variant (gene-first): 5290:p.Arg93Gln

Genes: 5290

Variants: p.Arg93Gln

[Paragraph-level] PMCID: PMC5019182 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses mutations of PIK3CA, including p.Glu545Lys and p.His1047Arg, which are identified as oncogenic mutations contributing to tumor development or progression, as indicated by their presence in the Catalogue of Somatic Mutations in Cancer (COSMIC). Functional: The passage mentions the alternative allele percentages (AAP) of the mutations, indicating that these variants may alter molecular or biochemical function, as evidenced by the variation in AAPs across different sample types.

Gene→Variant (gene-first): 5290:p.Glu545Lys 5290:p.His1047Arg

Genes: 5290

Variants: p.Glu545Lys p.His1047Arg