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

dbSNP: rs121913273

Total submissions: 22

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	2023-02-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Classified as pathogenic by the ClinGen Brain Malformations Variant Curation Expert Panel (SCV001949964.2); 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, 25044986, 29446767, 27631024, 26851524, 23100325, 23066039, 22658544, 22357840, 24374682, 33502802, 34606700)
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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513230	SCV003525379	pathogenic	Cowden syndrome	2022-10-27	criteria provided, single submitter	clinical testing	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. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 542 of the PIK3CA protein (p.Glu542Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PIK3CA-related disorders (PMID: 25599672, 26851524, 27631024). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 31944). For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458190	SCV004176951	pathogenic	PIK3CA related overgrowth syndrome	2023-11-03	criteria provided, single submitter	clinical testing	A PIK3CA c.1624G>A (p.Glu542Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Rodriguez-Laguna L et al., PMID: 29446767; Mirzaa G et al., PMID: 27631024; Osborn AJ et al., PMID: 25292196; Kurek KC et al., PMID: 22658544; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199). The PIK3CA c.1624G>A (p.Glu542Lys) variant has been classified as a pathogenic variant both in a germline and a somatic state by numerous laboratories as well as by an expert panel as a germline pathogenic variant (ClinVar Variation ID: 31944). This variant resides within the helical domain of the p110⍺ catalytic subunit, amino acids 517-694, of PIK3CA that is defined as a critical functional domain and constitutes a mutational hotspot (Madsen R et al., PMID: 30197175; Gymnopoulos M et al., PMID: 17376864). The PIK3CA c.1624G>A (p.Glu542Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies show that this lysine substitution at codon 542 leads to increased lipid kinase activity of p110a, autonomous phosphorylation of AKT, and oncogenic cellular transformation, indicating that this variant impacts protein function (Gymnopoulos M et al., PMID: 17376864; Ikenoue T et al., PMID: 15930273; Kang S et al., PMID: 15647370). The PIK3CA gene is defined by the ClinGen Brain Malformations Variant Curation 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 (Lai A et al., PMID: 35997716). A large number of PI3K/AKT pathway inhibitors are currently under clinical study, in both PROS disorders and cancer (Jin N et al., PMID: 34779417; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.1624G>A (p.Glu542Lys) variant is classified as pathogenic.
Genetics and Personalized Medicine Clinic, Tartu University Hospital	RCV004698785	SCV005199861	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome		criteria provided, single submitter	clinical testing
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	Ovarian neoplasm	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
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	Ovarian neoplasm	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	Abnormal 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
OMIM	RCV003764635	SCV004697482	pathogenic	HEMIFACIAL MYOHYPERPLASIA, SOMATIC	2012-06-08	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532404	SCV004717831	pathogenic	PIK3CA-related disorder	2024-07-24	no assertion criteria provided	clinical testing	The PIK3CA c.1624G>A variant is predicted to result in the amino acid substitution p.Glu542Lys. This is a recurrent somatic variant reported in individuals with dysplastic megalencephaly, hemimegalencephaly, or CLOVES syndrome (Kurek et al. 2012. PubMed ID: 22658544; Mirzaa et al. 2013. PubMed ID: 23946963; D’Gama et al. 2015. PubMed ID: 25599672; Mirzaa et al. 2016. PubMed ID: 27631024). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/31944/). This variant is interpreted as pathogenic.
GenomeConnect - Brain Gene Registry	RCV003987334	SCV004804559	not provided	PIK3CA-related overgrowth		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 06-14-2017 by Clinical Genomics Lab at Washington University in St. Louis. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527296	SCV005038938	likely pathogenic	Rare venous malformation	2024-03-19	no assertion criteria provided	clinical testing
Institute of Tissue Medicine and Pathology, University of Bern	RCV000024622	SCV005038939	likely pathogenic	CLOVES syndrome	2024-03-19	no assertion criteria provided	clinical testing