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Cowden syndrome (CS) is an autosomal dominant multiple hamartoma syndrome with elevated lifetime risks of breast and thyroid cancers. While germline PTEN mutations underlie the majority of cases, a subset of PTEN-negative individuals harbour mutations in other pathway genes. Recent data establish a role for PIK3CA in CS susceptibility (PMID:23246288).
Clinical validity is rated as Moderate based on identification of PIK3CA variants in 8 of 91 unrelated CS patients without PTEN mutations (PMID:23246288), with no reported familial segregation. Functional assays in patient‐derived cells demonstrate pathway activation consistent with PIK3CA gain of function.
Genetic evidence supports an autosomal dominant mode of inheritance. In the cohort, 10 distinct germline PIK3CA mutations were observed (7 missense, 1 nonsense, 2 indels), including the recurrent variant c.1145G>A (p.Arg382Lys) (PMID:23246288). No segregation data were available from family studies.
Functional studies reveal that CS‐associated PIK3CA mutations induce significantly increased phosphorylation of AKT at Thr308 and elevated cellular PIP3 levels, mirroring the biochemical consequences of oncogenic PIK3CA variants and supporting a gain‐of‐function mechanism (PMID:23246288).
No conflicting evidence has been reported to date regarding PIK3CA’s role in CS beyond the initial PTEN paradigm. The absence of PTEN mutations in these individuals reduces the likelihood of alternative genetic causes within the canonical PTEN‐AKT pathway.
Together, genetic and functional data converge to implicate PIK3CA as a moderate‐strength CS susceptibility gene. Incorporation of PIK3CA into diagnostic CS gene panels may enhance detection in PTEN‐negative cases. Key take‐home: Germline PIK3CA mutations account for ~9% of PTEN‐negative Cowden syndrome and drive pathway activation, informing both genetic testing and potential targeted intervention.
Gene–Disease AssociationModerate8 probands reported with germline PIK3CA variants (PMID:23246288) without PTEN mutations; functional data concordant Genetic EvidenceModerate8 unrelated probands with diverse PIK3CA variant types (7 missense, 1 nonsense, 2 indels) (PMID:23246288) Functional EvidenceModerateIncreased P-Thr308-AKT phosphorylation and PIP3 production observed in patient cells with PIK3CA mutations (PMID:23246288) |