Submissions for variant NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)

dbSNP: rs121913273

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Brain Malformations Variant Curation Expert Panel	RCV001836714	SCV001949964	pathogenic	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	2022-02-12	reviewed by expert panel	curation	The c.1624G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu542Lys). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 22658544). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 25722288, 25681199, 22658544, 29446767, 26851524, 25292196, 23100325; identified in 1 individual with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation, at least 6 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), at least 9 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, and at least 9 tumor samples in the literature and COSMIC). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PS2_M, PS4_VS, PM2_P, PP2; 12 points (VCEP specifications version 1; Approved: 1/31/2021)
GeneDx	RCV000416776	SCV001830827	pathogenic	not provided	2021-01-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25599672, 24374682, 23100325, 25044986, 22357840, 22658544, 23066039, 26851524, 27631024, 29446767)
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000416776	SCV002525701	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing	This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963 and others). The p.E542K variant substitutes the glutamic acid at position 542 with lysine within the PIK helical domain of the PIK3CA protein (UniProt P42336). This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 26627007).
OMIM	RCV000024622	SCV000050488	pathogenic	CLOVES syndrome	2012-06-08	no assertion criteria provided	literature only
GeneReviews	RCV000024622	SCV000086942	pathologic	CLOVES syndrome	2013-08-15	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine	RCV000151649	SCV000199901	pathogenic	Neoplasm of ovary	2011-10-12	no assertion criteria provided	clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine	RCV000154513	SCV000204184	pathogenic	Non-small cell lung carcinoma	2011-10-12	no assertion criteria provided	clinical testing
Department of Medical Genetics,University of Szeged	RCV000416776	SCV000258982	pathogenic	not provided	2015-09-01	no assertion criteria provided	case-control
Database of Curated Mutations (DoCM)	RCV000154513	SCV000503916	pathogenic	Non-small cell lung carcinoma	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421639	SCV000503917	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431872	SCV000503918	pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442348	SCV000503919	pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000151649	SCV000503920	pathogenic	Neoplasm of ovary	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433007	SCV000503921	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445059	SCV000503922	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425548	SCV000503923	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435811	SCV000503924	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419905	SCV000503925	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426691	SCV000503926	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436932	SCV000503927	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419440	SCV000503928	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431000	SCV000503929	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441707	SCV000503930	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420078	SCV000503931	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430763	SCV000503932	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438815	SCV000503933	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
OMIM	RCV000709693	SCV000839593	pathogenic	CLAPO syndrome	2012-06-08	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000151649	SCV000923935	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Institute of Medical Sciences, Banaras Hindu University	RCV001255687	SCV001432252	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research
MAGI's Lab - Research,MAGI Group	RCV001327962	SCV001437638	pathogenic	Abnormality of cardiovascular system morphology		no assertion criteria provided	provider interpretation
James Bennett Lab,Seattle Childrens Research Institute	RCV001730477	SCV001960169	pathogenic	Cerebrofacial Vascular Metameric Syndrome (CVMS)	2021-09-30	no assertion criteria provided	clinical testing
OMIM	RCV001728093	SCV001976537	pathogenic	CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC	2012-06-08	no assertion criteria provided	literature only