Submissions for variant NM_006218.4(PIK3CA):c.3129G>T (p.Met1043Ile)

dbSNP: rs121913283

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000631214	SCV000752228	pathogenic	Cowden syndrome	2021-07-13	criteria provided, single submitter	clinical testing	This variant has been reported to be de novo in an individual affected with megalencephaly-capillary malformation syndrome (PMID: 22729224). ClinVar contains an entry for this variant (Variation ID: 217292). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 1043 of the PIK3CA protein (p.Met1043Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. Experimental studies have shown that this missense change increases PIK3CA basal kinase activity and lipid binding (PMID: 15930273, 22120714). For these reasons, this variant has been classified as Pathogenic.
Care4Rare-SOLVE, CHEO	RCV000201236	SCV003932127	pathogenic	PIK3CA related overgrowth syndrome		criteria provided, single submitter	research
GeneDx	RCV003320599	SCV004025748	pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	De novo variant with confirmed parentage in multiple patients with PIK3CA-related overgrowth and brain malformations spectrum disorder in the published literature (Riviere et al., 2012; Mirzaa et al., 2016) and mosaic variant in a patient with PIK3CA-related overgrowth and brain malformations spectrum disorder referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29883676, 26627007, 18628094, 18516290, 27631024, 33745098, 29707142, 29650325, 29453417, 22729224, 25157968, 15930273, 34693559, 22120714, 35468270, 36635288, 37456262, 36468132, Nasomyont[CaseReport], 36710374, 32398863, 35070505, 34638442, 35715244, 35359373, 35154272)
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000201236	SCV000255983	pathogenic	PIK3CA related overgrowth syndrome	2014-10-18	no assertion criteria provided	clinical testing
Database of Curated Mutations (DoCM)	RCV000442578	SCV000504942	likely pathogenic	Neoplasm of the large intestine	2015-07-14	no assertion criteria provided	literature only