Submissions for variant NM_006218.4(PIK3CA):c.1258T>C (p.Cys420Arg)

dbSNP: rs121913272

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154512	SCV000204183	pathogenic	Ovarian neoplasm	2010-10-08	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000024623	SCV001736961	pathogenic	CLOVES syndrome		criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526612	SCV001737042	pathogenic	Capillary malformation		criteria provided, single submitter	clinical testing
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz	RCV001705599	SCV001934207	pathogenic	Segmental undergrowth associated with lymphatic malformation	2021-04-06	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000709694	SCV001976698	pathogenic	CLAPO syndrome	2021-10-01	criteria provided, single submitter	clinical testing	PS1, PM1, PM2, PM5, PP2, PP3, PP5
CeGaT Center for Human Genetics Tuebingen	RCV002054475	SCV002497234	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PIK3CA: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP4, PS3:Supporting
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002054475	SCV002525710	pathogenic	not provided	2021-02-23	criteria provided, single submitter	clinical testing	This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome, including isolated lymphatic malformation (PMID: 25681199). PIK3CA variants associated with PROS, including this patient's alteration, overlap those reported as oncogenic variants found in multiple tumor types (cBioPortal and NCI's Genomic Data Commons cancer databases). The p.Cys420Arg replaces the cysteine at codon 420 with arginine within the C2 domain of the PIK3CA protein (UniProt P42336). Experimental studies have demonstrated that the p.Cys240Arg variant causes overactivation of the PI3K/AKT/mTOR pathway and increased proliferation in vitro (PMID: 26627007).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003588566	SCV004366246	pathogenic	Cowden syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 420 of the PIK3CA protein (p.Cys420Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PIK3CA-related overgrowth syndrome (PMID: 22658544, 24782230; Invitae). ClinVar contains an entry for this variant (Variation ID: 31945). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 15930273, 17376864, 18074223, 22120714, 22949682). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000024623	SCV000050489	pathogenic	CLOVES syndrome	2012-06-08	no assertion criteria provided	literature only
GeneReviews	RCV000024623	SCV000086941	not provided	CLOVES syndrome		no assertion provided	literature only
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000201232	SCV000255982	pathogenic	PIK3CA related overgrowth syndrome	2014-04-23	no assertion criteria provided	clinical testing
OMIM	RCV000709694	SCV000839594	pathogenic	CLAPO syndrome	2012-06-08	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000154512	SCV000924133	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MAGI's Lab - Research, MAGI Group	RCV001327960	SCV001437636	pathogenic	Abnormal cardiovascular system morphology		no assertion criteria provided	provider interpretation
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000709694	SCV002583378	pathogenic	CLAPO syndrome	2022-02-01	no assertion criteria provided	clinical testing
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527297	SCV005038930	likely pathogenic	Rare combined vascular malformation	2024-03-19	no assertion criteria provided	clinical testing