ClinVar

Description

Variant summary: PIK3CA c.277C>T (p.Arg93Trp) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-kinase, adaptor-binding domain (IPR003113) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246610 control chromosomes. c.277C>T has been reported in the literature as a frequently reported somatic variant in a variety of cancers, as a somatic variant in at-least two cases among cohorts of individuals with a broad spectrum of clinical phenotypes, including CLOVES syndrome (612918), MCAP, fibroadipose overgrowth, and isolated hemihyperplasia or macrodactyly, as a likely disruptive variant in cohorts of patients with neurodevelopmental disorders (NDDs) (example, Rudd_2011, Gripp_2017, Stessman_2017, Chen_2020, Ahn_2021). These report(s) do not provide unequivocal conclusions about association of the variant with PIK3CA-Associated Segmental Overgrowth. At least one publication reports experimental evidence evaluating an impact on protein function (Rudd_2011). The most pronounced variant effect results in a gain-of function hotspot mutant that leads to increased phosphorylation of AKT on serine 473. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.