ClinVar Miner

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

dbSNP: rs1057519929
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Total submissions: 16
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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).
Invitae RCV002524695 SCV003525471 pathogenic Cowden syndrome 2021-12-30 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 376478). 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. 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).
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.
Database of Curated Mutations (DoCM) RCV000426861 SCV000506921 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436699 SCV000506922 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419439 SCV000506923 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431022 SCV000506924 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438199 SCV000506925 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420013 SCV000506926 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430702 SCV000506927 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438786 SCV000506928 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418157 SCV000506929 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
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

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