VCV000419222.23 - ClinVar

NM_006218.4(PIK3CA):c.1093G>A (p.Glu365Lys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (7)

7 out of 9 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Likely oncogenic

This classification is based on the single submission received

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Variant Details

Identifiers

NM_006218.4(PIK3CA):c.1093G>A (p.Glu365Lys)

Variation ID: 419222 Accession: VCV000419222.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179204536 (GRCh38) [ NCBI UCSC ] 3: 178922324 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 27, 2017	Jun 20, 2026	Jun 5, 2025
Somatic - Oncogenicity	Jan 3, 2026	Jan 3, 2026	Dec 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.1093G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Glu365Lys	missense
NC_000003.12:g.179204536G>A
NC_000003.11:g.178922324G>A
NG_012113.2:g.61014G>A
LRG_310:g.61014G>A
LRG_310t1:c.1093G>A

... more HGVS ... less HGVS

Protein change

E365K

Other names

Canonical SPDI

NC_000003.12:179204535:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA16617848 dbSNP: rs1064793732 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PIK3CA		No evidence available	No evidence available	GRCh38 GRCh37	1650	1689

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 15, 2024	RCV000484163.3
Cowden syndrome	Pathogenic (2)	criteria provided, single submitter	Feb 20, 2023	RCV000798360.11
Ovarian neoplasm	Pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785369.3
Megalencephaly-capillary malformation-polymicrogyria syndrome	Pathogenic (1)	criteria provided, single submitter	-	RCV001526558.3
Angioosteohypertrophic syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 18, 2021	RCV002254298.2
PIK3CA-related disorder	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 5, 2025	RCV004535503.4
PIK3CA related overgrowth syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2024	RCV005251138.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Megalencephaly-capillary malformation-polymicrogyria syndrome	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001736983.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Pathogenic (Nov 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000566894.4 First in ClinVar: Apr 27, 2017 Last updated: Nov 24, 2024	Comment: show Published functional studies found this variant is associated with increased activation of the PI3K pathway (PMID: 18829572); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159, 27631024, 32960281, 33077954, 22729224, 18829572) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Feb 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cowden syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000937973.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 18829572‚ 22729224‚ 27631024 Comment: show This missense change has been observed in individual(s) with PIK3CA related overgrowth syndrome and megalencephaly-capillary malformation syndrome (MCAP) (PMID: 22729224, 27631024). 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 365 of the PIK3CA protein (p.Glu365Lys). ClinVar contains an entry for this variant (Variation ID: 419222). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 18829572). 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 18, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Angioosteohypertrophic syndrome	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV002525706.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: show Variants in this gene have previously been reported in numerous unrelated individuals with PIK3CA-related overgrowth spectrum (PROS) disorders, which includes Klippel-Trenaunay syndrome (PMID: 26268729). This variant has also been observed in individuals with megalencephaly and megalencephaly-capillary malformation syndrome (PMID: 27631024, PMID: 22729224). The p.E365K variant substitutes the glutamic acid at position 365 with lysine within the C2 domain of the PIK3CA protein. Mutations in this domain have been reported to enhance recruitment of phosphatidylinositol 3-kinase (PI3K) to the membrane, leading to constitutive pathway activation (PMID: 17376864). (less) Observation: 2 Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Hemihypertrophy of lower limb (present) , Predominantly lower limb lymphedema (present) , Menorrhagia (present) , Epistaxis (present) Observation 2 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Cerebral cavernous malformation (present) , Intracranial hemorrhage (present) , Seizure (present)

Pathogenic (Feb 02, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	PIK3CA-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004120984.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: show The PIK3CA c.1093G>A variant is predicted to result in the amino acid substitution p.Glu365Lys. This variant has been reported with de novo occurrence in several individuals with PIK3CA-related overgrowth phenotypes (See for example, Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Jin et al. 2020. PubMed ID: 33077954). In at least one of these individuals it was found to be mosaic (Mirzaa et al. 2016. PubMed ID: 27631024). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Leon-Quintero et al. (Clin Genet. 2025))	PIK3CA-related overgrowth syndrome	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV005902170.1 First in ClinVar: Apr 07, 2025 Last updated: Apr 07, 2025	Comment: show A PIK3CA c.1093G>A (p.Glu365Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth spectrum (PROS) disorders (Sasaki Y et al., PMID: 37667289; McNulty SN et al., PMID: 31585106; Mirzaa G et al., PMID: 27631024; Rivière JB et al., PMID: 22729224). This variant has also been reported in the ClinVar database as pathogenic in both a somatic and a germline state by several submitters (ClinVar Variation ID: 419222) and has been reported as a somatic variant in numerous cases in the cancer database COSMIC (Genomic Mutation ID: COSV55881636). It is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The PIK3CA c.1093G>A (p.Glu365Lys) variant, resides within a region, the C2 domain, of PIK3CA that is defined as a critical functional domain (Lai A et al., PMID: 35997716). Functional studies show that this lysine substitution at codon 365 leads to increased lipid kinase activity resulting in constitutive PI3K signaling (Oda K et al., PMID: 18829572). The PIK3CA gene 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 (Lai A et al., PMID: 35997716). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.1093G>A (p.Glu365Lys) variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Pathogenic (Jun 05, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	PIK3CA-related disorder	3billion Accession: SCV006582149.2 First in ClinVar: Oct 25, 2025 Last updated: Jun 20, 2026	Publications: PubMed (1) PubMed: 22729224 Comment: show The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 26637981, 24459181, 27631024). Missense variant. Missense changes are a common disease-causing mechanism. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000419222 /PMID: 22729224 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Platform type: exome sequencing

Pathogenic (Dec 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Ovarian neoplasm	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV000923940.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Observation: 1 Collection method: research Allele origin: somatic Affected status: yes more Observation 1 Collection method: research Allele origin: somatic Affected status: yes Platform type: next-gen sequencing

Pathogenic (Oct 19, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Cowden syndrome	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106926.1 First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 2022	Publications: PubMed (1) PubMed: 33077954 Observation: 1 Collection method: literature only Allele origin: de novo Affected status: yes more Observation 1 Collection method: literature only Allele origin: de novo Affected status: yes Zygosity: 1 Single Heterozygote

Comment:

Published functional studies found this variant is associated with increased activation of the PI3K pathway (PMID: 18829572); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159, 27631024, 32960281, 33077954, 22729224, 18829572)

Comment:

This missense change has been observed in individual(s) with PIK3CA related overgrowth syndrome and megalencephaly-capillary malformation syndrome (MCAP) (PMID: 22729224, 27631024). 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 365 of the PIK3CA protein (p.Glu365Lys). ClinVar contains an entry for this variant (Variation ID: 419222). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 18829572). 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.

Comment:

Variants in this gene have previously been reported in numerous unrelated individuals with PIK3CA-related overgrowth spectrum (PROS) disorders, which includes Klippel-Trenaunay syndrome (PMID: 26268729). This variant has also been observed in individuals with megalencephaly and megalencephaly-capillary malformation syndrome (PMID: 27631024, PMID: 22729224). The p.E365K variant substitutes the glutamic acid at position 365 with lysine within the C2 domain of the PIK3CA protein. Mutations in this domain have been reported to enhance recruitment of phosphatidylinositol 3-kinase (PI3K) to the membrane, leading to constitutive pathway activation (PMID: 17376864).

Comment:

The PIK3CA c.1093G>A variant is predicted to result in the amino acid substitution p.Glu365Lys. This variant has been reported with de novo occurrence in several individuals with PIK3CA-related overgrowth phenotypes (See for example, Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Jin et al. 2020. PubMed ID: 33077954). In at least one of these individuals it was found to be mosaic (Mirzaa et al. 2016. PubMed ID: 27631024). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Comment:

A PIK3CA c.1093G>A (p.Glu365Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth spectrum (PROS) disorders (Sasaki Y et al., PMID: 37667289; McNulty SN et al., PMID: 31585106; Mirzaa G et al., PMID: 27631024; Rivière JB et al., PMID: 22729224). This variant has also been reported in the ClinVar database as pathogenic in both a somatic and a germline state by several submitters (ClinVar Variation ID: 419222) and has been reported as a somatic variant in numerous cases in the cancer database COSMIC (Genomic Mutation ID: COSV55881636). It is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The PIK3CA c.1093G>A (p.Glu365Lys) variant, resides within a region, the C2 domain, of PIK3CA that is defined as a critical functional domain (Lai A et al., PMID: 35997716). Functional studies show that this lysine substitution at codon 365 leads to increased lipid kinase activity resulting in constitutive PI3K signaling (Oda K et al., PMID: 18829572). The PIK3CA gene 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 (Lai A et al., PMID: 35997716). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.1093G>A (p.Glu365Lys) variant is classified as pathogenic.

Comment:

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 26637981, 24459181, 27631024). Missense variant. Missense changes are a common disease-causing mechanism. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000419222 /PMID: 22729224 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.	Jin SC	Nature medicine	2020	PMID: 33077954
PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.	Mirzaa G	JCI insight	2016	PMID: 27631024
De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.	Rivière JB	Nature genetics	2012	PMID: 22729224
PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation.	Oda K	Cancer research	2008	PMID: 18829572

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Likely oncogenic criteria provided, single submitter	Dec 29, 2025	RCV006273822.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Likely oncogenic (Dec 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)	Neoplasm	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV007130018.1 First In ClinVar: Jan 03, 2026 Last updated: Jan 03, 2026	Publications: PubMed (3) PubMed: 18829572‚ 21266528‚ 29533785 Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Systematic Functional Annotation of Somatic Mutations in Cancer.	Ng PK	Cancer cell	2018	PMID: 29533785
A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas.	Rudd ML	Clinical cancer research : an official journal of the American Association for Cancer Research	2011	PMID: 21266528
PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation.	Oda K	Cancer research	2008	PMID: 18829572

Text-mined citations for rs1064793732 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 06, 2026