Submissions for variant NM_006218.4(PIK3CA):c.2740G>A (p.Gly914Arg)

dbSNP: rs587776932

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Brain Malformations Variant Curation Expert Panel	RCV001836717	SCV001949968	pathogenic	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	2022-02-12	reviewed by expert panel	curation	The c.2740G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Gly914Arg). 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). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; identified in 5 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), and in 4 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 22729224), and it was identified in 2 tumor samples in COSMIC (PMID: 22729224, PMID: 28151489, PMID: 28502725, PMID: 30231930). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMID: 22729224). 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: PM2_P, PP2, PM1_P, PS4, PS2; 11 points (VCEP specifications version 1; Approved: 1/31/2021)
UCLA Clinical Genomics Center, UCLA	RCV000032907	SCV000255436	likely pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2013-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000414672	SCV000490720	pathogenic	not provided	2022-07-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22729224, 24939587, 25106414, 23592320, 27631024, 28151489, 28737257, 29346770, 30231930, 32608066, 32595695, 33942430, 33415748, 32778138, 33604570, 34066481, 34097172, 31677919, 33105631, 31729162, 32042194, 33077954, 27535533)
Baylor Genetics	RCV000032907	SCV000807308	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found twice in our laboratory in individuals with overgrowth, macrocephaly, hemihypertrophy, and polydactyly or syndactyly
CeGaT Center for Human Genetics Tuebingen	RCV000414672	SCV001248956	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV001594376	SCV001499939	likely pathogenic	Cowden syndrome 5	2020-12-20	criteria provided, single submitter	clinical testing
Invitae	RCV001852661	SCV002140112	pathogenic	Cowden syndrome	2023-08-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 39703). This missense change has been observed in individual(s) with PIK3CA-related overgrowth spectrum (PROS) (PMID: 22729224, 27631024, 30231930, 32595695). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 914 of the PIK3CA protein (p.Gly914Arg).
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002254272	SCV002525702	pathogenic	Angioosteohypertrophic syndrome	2019-12-16	criteria provided, single submitter	clinical testing	This variant substitutes the glycine at position 941 with arginine within the kinase domain of the PIK3CA protein. This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 22729224, PMID: 27631024, PMID: 28151489, PMID: 30231930).
Care4Rare-SOLVE, CHEO	RCV003233078	SCV003932124	pathogenic	PIK3CA related overgrowth syndrome		criteria provided, single submitter	research
OMIM	RCV000032907	SCV000056679	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2012-06-24	no assertion criteria provided	literature only
MAGI's Lab - Research, MAGI Group	RCV001327966	SCV001437642	pathogenic	Abnormal cardiovascular system morphology		no assertion criteria provided	provider interpretation
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414672	SCV001956173	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000414672	SCV001974335	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000032907	SCV002106923	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2020-10-19	no assertion criteria provided	literature only
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274888	SCV002562835	pathogenic	Abnormal cerebral morphology		no assertion criteria provided	clinical testing