Submissions for variant NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)

dbSNP: rs1057519925

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000991209	SCV001142587	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2019-05-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000991209	SCV001521015	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2020-06-25	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526693	SCV001737114	pathogenic	CLOVES syndrome		criteria provided, single submitter	clinical testing
GeneDx	RCV001775789	SCV002013346	pathogenic	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: increased phosphorylation of AKT on serine 473 (Rudd et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23352210, 29759595, 26619011, 21531001, 27834349, 27631024, 30063105, 27037860, 31263565, 21266528)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861479	SCV002247469	pathogenic	Cowden syndrome	2021-06-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with PIK3CA-associated overgrowth conditions (PMID: 27631024, 27631024, 28151489, ClinVar). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376470). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 453 of the PIK3CA protein (p.Glu453Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Daryl Scott Lab, Baylor College of Medicine	RCV002244865	SCV002515365	pathogenic	PIK3CA-related disorder	2022-02-01	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV001775789	SCV002525708	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	This variant has previously been reported in multiple unrelated individuals with a molecular diagnosis of PROS, including those with reported overgrowth and macrodactyly (PMID: 27631024, PMID: 31263565). The p.Glu453Lys variant substitutes the glutamic acid at position 453 with lysine within the C2 phosphatidylinositol 3-kinase domain of the PIK3CA protein (UniProt P42336, aa# 330-487). This is a recurrent hotspot. PIK3CA variants associated with PROS overlap those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472374	SCV002557944	pathogenic	PIK3CA related overgrowth syndrome	2022-09-02	criteria provided, single submitter	clinical testing	A suspected mosaic missense variant was identified, NM_006218.2(PIK3CA):c.1357G>A in exon 8 of the PIK3CA gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to a lysine at position 453 of the protein; NP_006209.2(PIK3CA):p.(Glu453Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located within the C2 domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in patients with overgrowth disorders (Mirzaa, G. et al . (2016); Piacitelli, A. et al . (2018)). A different variant in the same codon resulting in an inframe deletion has also been shown to cause the same condition (Mirzaa, G. et al . (2016); Riviere, J-B. et al . (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV001526693	SCV003928007	pathogenic	CLOVES syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. somatic mutation
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000991209	SCV005395938	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2024-07-10	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785580	SCV000924154	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MAGI's Lab - Research, MAGI Group	RCV001327961	SCV001437637	pathogenic	Abnormal cardiovascular system morphology		no assertion criteria provided	provider interpretation