Submissions for variant NM_006218.4(PIK3CA):c.241G>A (p.Glu81Lys)

dbSNP: rs1057519929

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526599	SCV001737028	pathogenic	CLOVES syndrome		criteria provided, single submitter	clinical testing
GeneDx	RCV001837893	SCV002098175	pathogenic	not provided	2023-06-08	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: 28502730, 34758253, 25915946, 26619011, 23592320, 29549527, 27798902, 21531001, 29493003, 33539671, 34969754, 34779417, 32923889, 24037760, 33503190, 33442366, 30243889, 33105631, 32235312, 22729224, 29575851, 29643510, 34684076, 34736091, 34150029)
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV001837893	SCV002525572	pathogenic	not provided	2020-12-29	criteria provided, single submitter	clinical testing	This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31585106, PMID: 22729224, PMID: 25915946). 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.Glu81Lys replaces the glycine at codon 81 with lysine within the PI3K adaptor-binding domain of the protein (UniProt P42336). Experimental studies have demonstrated that the p.Glu81Lys variant causes overactivation of the PI3K/AKT/mTOR pathway (PMID: 25915946).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524695	SCV003525471	pathogenic	Cowden syndrome	2021-12-30	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) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CA protein function. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 81 of the PIK3CA protein (p.Glu81Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PIK3CA-related overgrowth spectrum (PMID: 22729224, 25915946). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376478). For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458199	SCV004176917	pathogenic	PIK3CA related overgrowth syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The PIK3CA c.241G>A (p.Glu81Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected by PROS disorders (Rivière JB et al., PMID: 22729224; Loconte DC et al., PMID: 25915946; Kuentz P et al., PMID: 28151489; Leiter SM et al., PMID: 28566443; Zhang M et al., PMID: 30996962; Mirzaa GM et al., PMID: 23592320; Denorme P et al., PMID: 29493003; Paolacci S et al., PMID: 33105631; Ranieri C et al., PMID: 29549527). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic by multiple submitters in both a somatic and germline state (ClinVar ID: 376478) and in multiple cases in the cancer database COSMIC (ID: COSV55873676). This variant is absent from the general population database (gnomAD v.3.1.2), indicating that it is not a common variant. This variant resides within a p85-binding domain, amino acids 32-107, of PIK3CA that is defined as a critical functional domain (Burke JE et al., PMID: 22949682; Zhang M et al., PMID: 30996962). Functional in vitro studies show that this variant induces Akt-mTOR signaling and enhanced cell growth, indicating that this variant impacts protein function (Jin N et al., PMID: 34779417; Loconte DC et al., PMID: 25915946). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. The PIK3CA gene is defined by ClinGen's Brain Malformation expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Lai et al., PMID: 35997716). 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.241G>A (p.Glu81Lys) variant is classified as pathogenic.
MAGI's Lab - Research, MAGI Group	RCV001327958	SCV001437634	pathogenic	Abnormal cardiovascular system morphology		no assertion criteria provided	provider interpretation
Genomics England Pilot Project, Genomics England	RCV001542570	SCV001760113	likely pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome		no assertion criteria provided	clinical testing