VCV000031944.42 - ClinVar

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

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Classification is based on the expert panel submission

Feb 2022 by ClinGen Brain Malformations Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

Clinical impact

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

Tier I (Strong) for 4 tumor types

+lower levels of evidence for Alveolar rhabdomyosarcoma

4 out of 6 submissions contributed to this classification

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

Oncogenicity

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

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.1624G>A (p.Glu542Lys)

Variation ID: 31944 Accession: VCV000031944.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.32 3: 179218294 (GRCh38) [ NCBI UCSC ] 3: 178936082 (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	Oct 1, 2013	Feb 15, 2026	Feb 12, 2022
Somatic - Clinical impact	Nov 22, 2025	Feb 7, 2026	Oct 7, 2025
Somatic - Oncogenicity	Aug 11, 2024	Mar 11, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_006218.4:c.1624G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006209.2:p.Glu542Lys	missense
NC_000003.12:g.179218294G>A
NC_000003.11:g.178936082G>A
NG_012113.2:g.74772G>A
LRG_310:g.74772G>A
LRG_310t1:c.1624G>A
	P42336:p.Glu542Lys

... more HGVS ... less HGVS

Protein change

E542K

Other names

NM_006218.3(PIK3CA):c.1624G>A
NM_006218.4(PIK3CA):c.1624G>A

Canonical SPDI

NC_000003.12:179218293: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: CA333572 UniProtKB: P42336#VAR_026173 OMIM: 171834.0009 dbSNP: rs121913273 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	1655	1695

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.
CLOVES syndrome	Pathogenic/Likely pathogenic (3)	no assertion criteria provided	Mar 19, 2024	RCV000024622.23
Ovarian neoplasm	Pathogenic (2)	no assertion criteria provided	Dec 1, 2018	RCV000151649.16
Non-small cell lung carcinoma	Pathogenic (1)	no assertion criteria provided	Oct 12, 2011	RCV000154513.15
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 27, 2023	RCV000416776.16
CLAPO syndrome	Pathogenic (1)	no assertion criteria provided	Jun 8, 2012	RCV000709693.14
Abnormal cardiovascular system morphology	Pathogenic (1)	no assertion criteria provided	-	RCV001327962.9
Lip and oral cavity carcinoma	Pathogenic (1)	no assertion criteria provided	Apr 30, 2019	RCV001255687.9
Cerebrofacial Vascular Metameric Syndrome (CVMS)	Pathogenic (1)	no assertion criteria provided	Sep 30, 2021	RCV001730477.10
CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC	Pathogenic (1)	no assertion criteria provided	Jun 8, 2012	RCV001728093.12
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	Pathogenic (1)	reviewed by expert panel	Feb 12, 2022	RCV001836714.10
Cowden syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 27, 2022	RCV002513230.12
HEMIFACIAL MYOHYPERPLASIA, SOMATIC	Pathogenic (1)	no assertion criteria provided	Jun 8, 2012	RCV003764635.2
PIK3CA related overgrowth syndrome	Pathogenic (1)	criteria provided, single submitter	Nov 3, 2023	RCV003458190.2
PIK3CA-related overgrowth	not provided (1)	no classification provided	-	RCV003987334.3
PIK3CA-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 24, 2024	RCV004532404.3
Rare venous malformation	Likely pathogenic (1)	no assertion criteria provided	Mar 19, 2024	RCV004527296.1
Megalencephaly-capillary malformation-polymicrogyria syndrome	Pathogenic (1)	criteria provided, single submitter	-	RCV004698785.2
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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 (Feb 12, 2022) C Contributing to aggregate classification	reviewed by expert panel (ClinGen BrainMalform ACMG Specifications v1)	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (Autosomal dominant inheritance)	ClinGen Brain Malformations Variant Curation Expert Panel FDA Recognized Database Accession: SCV001949964.2 First in ClinVar: Oct 02, 2021 Last updated: Feb 20, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7ffcf400-d46a-4637-be35-8721447aa249 Comment: show 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) (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Nov 03, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	PIK3CA-related overgrowth syndrome	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176951.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: show 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. (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 (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Megalencephaly-capillary malformation-polymicrogyria syndrome	Genetics and Personalized Medicine Clinic, Tartu University Hospital Accession: SCV005199861.2 First in ClinVar: Sep 08, 2024 Last updated: Apr 13, 2025	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 Clinical Features: Lymphangioma (present) , 3-4 toe syndactyly (present) , Macrodactyly of toe (present) Comment on clinical features: Lymphangiomas on the left thigh and both upper limbs, Multicystic lymphangiomas in the abdominal cavity, Antenatal cystic formation in the pelvis, syndactyly of T3-4 on the right and left foot, Macrodactyly of left foot Age: 0-9 years Sex: female Ethnicity/Population group: Estonian

Pathogenic (Oct 01, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV002525701.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: show 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). (less) Observation: 22 Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Venous malformation (present) Observation 2 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormality of the vasculature (present) , Facial asymmetry (present) , Multiple lipomas (present) Observation 3 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) , Eczematoid dermatitis (present) , Dental malocclusion (present) , Facial asymmetry (present) Observation 4 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) Observation 5 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) , Cerebral venous angioma (present) , Abnormal vascular morphology (present) , Headache (present) Observation 6 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) , Venous malformation (present) , Overgrowth (present) Observation 7 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) Observation 8 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) , Capillary malformation (present) , Congenital macrodactylia (present) , Nevus (present) , Abnormality of the upper limb (present) , Abnormality of the shoulder girdle musculature (present) Observation 9 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 10 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 11 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 12 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 13 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) Observation 14 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) Observation 15 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) Observation 16 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 17 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 18 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 19 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Observation 20 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Abnormal lymphatic vessel morphology (present) Observation 21 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1 Clinical Features: Lymphangioma (present) Observation 22 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Clinical Features: Overgrowth (present) , Capillary malformation (present)

Pathogenic (Feb 27, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001830827.4 First in ClinVar: Sep 08, 2021 Last updated: Mar 11, 2023	Comment: show 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) (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 (Oct 27, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cowden syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003525379.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 25599672‚ 26851524‚ 27631024 Comment: show 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: 31944). 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. 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 542 of the PIK3CA protein (p.Glu542Lys). (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 (Oct 12, 2011) N Not contributing to aggregate classification	no assertion criteria provided	Ovarian Cancer	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000199901.1 First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: not provided Number of individuals with the variant: 2

Pathogenic (Oct 12, 2011) N Not contributing to aggregate classification	no assertion criteria provided	Non-Small Cell Lung Cancer	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204184.1 First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: not provided Number of individuals with the variant: 7

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: SCV000923935.1 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 (Jun 08, 2012) N Not contributing to aggregate classification	no assertion criteria provided	CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI, SOMATIC	OMIM Accession: SCV000050488.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (4) PubMed: 22658544‚ 29446767‚ 34496175‚ 37712948 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided Comment on evidence: CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A … (more) CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A transition in the PIK3CA gene, resulting in a glu542-to-lys (E542K) substitution that was present in affected tissues from multiple embryonic lineages with a mutant allele frequency ranging from 6 to 13%. CLAPO Syndrome In tissue from a lower lip capillary malformation (CM) from a 2-year-old female patient (P10) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) identified a c.1624G-A transition (c.1624G-A, NM_006218.2) in the PIK3CA gene that resulted in a glu542-to-lys (E542K) mutation in the helical domain. The mutation was present at an allele frequency of 10% by deep sequencing, was present in 999 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 44 patients with vascular overgrowth disorders. Functional studies were not performed. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 16 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic E542K mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Hemifacial Myohyperplasia In 2 patients (patients 3 and 4) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E542K mutation in the PIK3CA gene. Bayard et al. (2023) performed genotyping on muscle biopsies from affected regions and found a mutation burden of 12% in patient 3 and 21% in patient 4. (less)

Pathogenic (Jun 08, 2012) N Not contributing to aggregate classification	no assertion criteria provided	CAPILLARY MALFORMATION OF THE LOWER LIP, LYMPHATIC MALFORMATION OF FACE AND NECK, ASYMMETRY OF FACE AND LIMBS, AND PARTIAL/GENERALIZED OVERGROWTH, SOMATIC	OMIM Accession: SCV000839593.4 First in ClinVar: Oct 14, 2018 Last updated: Mar 10, 2024	Publications: PubMed (4) PubMed: 22658544‚ 29446767‚ 34496175‚ 37712948 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided Comment on evidence: CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A … (more) CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A transition in the PIK3CA gene, resulting in a glu542-to-lys (E542K) substitution that was present in affected tissues from multiple embryonic lineages with a mutant allele frequency ranging from 6 to 13%. CLAPO Syndrome In tissue from a lower lip capillary malformation (CM) from a 2-year-old female patient (P10) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) identified a c.1624G-A transition (c.1624G-A, NM_006218.2) in the PIK3CA gene that resulted in a glu542-to-lys (E542K) mutation in the helical domain. The mutation was present at an allele frequency of 10% by deep sequencing, was present in 999 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 44 patients with vascular overgrowth disorders. Functional studies were not performed. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 16 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic E542K mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Hemifacial Myohyperplasia In 2 patients (patients 3 and 4) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E542K mutation in the PIK3CA gene. Bayard et al. (2023) performed genotyping on muscle biopsies from affected regions and found a mutation burden of 12% in patient 3 and 21% in patient 4. (less)

Pathogenic (Jun 08, 2012) N Not contributing to aggregate classification	no assertion criteria provided	CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC	OMIM Accession: SCV001976537.2 First in ClinVar: Oct 08, 2021 Last updated: Mar 10, 2024	Publications: PubMed (4) PubMed: 22658544‚ 29446767‚ 34496175‚ 37712948 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided Comment on evidence: CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A … (more) CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A transition in the PIK3CA gene, resulting in a glu542-to-lys (E542K) substitution that was present in affected tissues from multiple embryonic lineages with a mutant allele frequency ranging from 6 to 13%. CLAPO Syndrome In tissue from a lower lip capillary malformation (CM) from a 2-year-old female patient (P10) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) identified a c.1624G-A transition (c.1624G-A, NM_006218.2) in the PIK3CA gene that resulted in a glu542-to-lys (E542K) mutation in the helical domain. The mutation was present at an allele frequency of 10% by deep sequencing, was present in 999 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 44 patients with vascular overgrowth disorders. Functional studies were not performed. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 16 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic E542K mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Hemifacial Myohyperplasia In 2 patients (patients 3 and 4) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E542K mutation in the PIK3CA gene. Bayard et al. (2023) performed genotyping on muscle biopsies from affected regions and found a mutation burden of 12% in patient 3 and 21% in patient 4. (less)

Pathogenic (Jun 08, 2012) N Not contributing to aggregate classification	no assertion criteria provided	HEMIFACIAL MYOHYPERPLASIA, SOMATIC	OMIM Accession: SCV004697482.2 First in ClinVar: Mar 05, 2024 Last updated: Mar 10, 2024	Publications: PubMed (4) PubMed: 22658544‚ 29446767‚ 34496175‚ 37712948 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided Comment on evidence: CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A … (more) CLOVE Syndrome In a 14-year-old girl and an unrelated 1-year-old boy with CLOVE syndrome (612918), Kurek et al. (2012) identified somatic mosaicism for a 1624G-A transition in the PIK3CA gene, resulting in a glu542-to-lys (E542K) substitution that was present in affected tissues from multiple embryonic lineages with a mutant allele frequency ranging from 6 to 13%. CLAPO Syndrome In tissue from a lower lip capillary malformation (CM) from a 2-year-old female patient (P10) with CLAPO syndrome (613089), Rodriguez-Laguna et al. (2018) identified a c.1624G-A transition (c.1624G-A, NM_006218.2) in the PIK3CA gene that resulted in a glu542-to-lys (E542K) mutation in the helical domain. The mutation was present at an allele frequency of 10% by deep sequencing, was present in 999 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and had been previously reported in 44 patients with vascular overgrowth disorders. Functional studies were not performed. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 16 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic E542K mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Hemifacial Myohyperplasia In 2 patients (patients 3 and 4) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E542K mutation in the PIK3CA gene. Bayard et al. (2023) performed genotyping on muscle biopsies from affected regions and found a mutation burden of 12% in patient 3 and 21% in patient 4. (less)

Pathogenic (Jul 24, 2024) N Not contributing to aggregate classification	no assertion criteria provided	PIK3CA-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004717831.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show 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. (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 (Sep 30, 2021) N Not contributing to aggregate classification	no assertion criteria provided	Cerebrofacial Vascular Metameric Syndrome (CVMS) (Somatic mutation)	James Bennett Lab, Seattle Childrens Research Institute Accession: SCV001960169.2 First in ClinVar: Oct 21, 2021 Last updated: Aug 03, 2025	Publications: PubMed (3) PubMed: 22658544‚ 26627007‚ 31536475 Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Comment on evidence: "gain_of_function_variant" was previously submitted as the functional consequence for NM_006218.4:c.1624G>A, but without providing the result of a functional assay.

Pathogenic (Apr 30, 2019) N Not contributing to aggregate classification	no assertion criteria provided	Lip and oral cavity carcinoma	Institute of Medical Sciences, Banaras Hindu University Accession: SCV001432252.1 First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020	Publications: PubMed (1) PubMed: 31775759 Observation: 1 Collection method: research Allele origin: somatic Affected status: yes Observation 1 Collection method: research Allele origin: somatic Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Abnormal cardiovascular system morphology	MAGI's Lab - Research, MAGI Group Accession: SCV001437638.1 First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021	Observation: 2 Observation 1 Collection method: provider interpretation Allele origin: somatic Affected status: yes Observation 2 Collection method: provider interpretation Allele origin: somatic Affected status: yes

Likely pathogenic (Mar 19, 2024) N Not contributing to aggregate classification	no assertion criteria provided	Rare venous malformation	Institute of Tissue Medicine and Pathology, University of Bern Accession: SCV005038938.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 5

Likely pathogenic (Mar 19, 2024) N Not contributing to aggregate classification	no assertion criteria provided	CLOVES syndrome	Institute of Tissue Medicine and Pathology, University of Bern Accession: SCV005038939.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Number of individuals with the variant: 1

Pathogenic (Sep 01, 2015) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Department of Medical Genetics, University of Szeged Accession: SCV000258982.2 First in ClinVar: Feb 10, 2017 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 26851524 Observation: 1 Collection method: case-control Allele origin: somatic Affected status: yes more Observation 1 Collection method: case-control Allele origin: somatic Affected status: yes Clinical Features: Macrodactyly of fingers (present) Indication for testing: Macrodactyly of fingers Zygosity: 1 Single Heterozygote Family history: no Age: 0-9 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Hungary Tissue: soft tissue Number of individuals demonstrating mosaicism for the variant: 1

Pathogenic (Aug 15, 2013) N Not contributing to aggregate classification	no assertion criteria provided	PIK3CA-Related Segmental Overgrowth	GeneReviews Accession: SCV000086942.2 First in ClinVar: Oct 01, 2013 Last updated: Jun 08, 2025	Comment: show Converted during submission from pathologic to Pathogenic. (less) Observation: 1 Collection method: curation Allele origin: unknown Affected status: not provided Observation 1 Collection method: curation Allele origin: unknown Affected status: not provided

not provided (-) N Not contributing to aggregate classification	no classification provided	PIK3CA-related overgrowth	GenomeConnect - Brain Gene Registry Accession: SCV004804559.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 13, 2025	Comment: show 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/. (less) Observation: 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown more Observation 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Clinical Features: Cystic hygroma (present) , Abnormality of the lymphatic system (present) , Developmental dysplasia of the hip (present) Zygosity: 1 Single Heterozygote Age: 0-9 years Sex: female Method: Single Gene Sequencing Testing laboratory: Clinical Genomics Laboratory, Washington University in St. Louis Date variant was reported to submitter: 2017-06-14 Testing laboratory interpretation: Pathogenic

Comment:

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)

Comment:

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.

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 28966033, 24705251, 29763623, 28912153, 25219808).

Comment:

Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in alveolar rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 24436047, 34166060, 24332040, 25768946).

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in rosette-forming glioneuronal tumor of fourth ventricule, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 31250151, 32859279, 21997360, 23547894, 24806303, 27893178, 28912153).

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in glioma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 32289278, 28912153, 35332262).

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in vascular malformation, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 26627007, 16432179, 17376864). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 25681199, 29217067, 31536475).

Comment:

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).

Comment:

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)

Comment:

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: 31944). 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. 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 542 of the PIK3CA protein (p.Glu542Lys).

Comment:

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.

Comment:

Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in cervical squamous cell carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 18268322; 39717717). 3) Diagnostic significance for this tumor based on multiple studies (Evidence Level C; PMIDs: 28112728; 29892689; 32653099; 35568000).

Comment:

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/.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition.	Bayard C	The Journal of experimental medicine	2023	PMID: 37712948
PIK3CA-Related Overgrowth Spectrum.	Adam MP	-	2023	PMID: 23946963
Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations.	Peyre M	The New England journal of medicine	2021	PMID: 34496175
Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations.	Zenner K	JCI insight	2019	PMID: 31536475
CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype.	Rodriguez-Laguna L	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29446767
PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.	Mirzaa G	JCI insight	2016	PMID: 27631024
Somatic mosaicism of the PIK3CA gene identified in a Hungarian girl with macrodactyly and syndactyly.	Tripolszki K	European journal of medical genetics	2016	PMID: 26851524
Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations.	Dogruluk T	Cancer research	2015	PMID: 26627007
Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia.	D'Gama AM	Annals of neurology	2015	PMID: 25599672
Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.	Kurek KC	American journal of human genetics	2012	PMID: 22658544
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7ffcf400-d46a-4637-be35-8721447aa249	-	-	-	-
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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		Oncogenic criteria provided, single submitter	Mar 4, 2025	RCV004668742.2
Glioma	Tier I (Strong) - diagnostic - supports diagnosis (1)		Mar 24, 2025	RCV006253683.1
Cervical squamous cell carcinoma	Tier II (Potential) - diagnostic - supports diagnosis (1)		Nov 30, 2025	RCV006456623.1
Alveolar rhabdomyosarcoma	Tier II (Potential) - diagnostic - supports diagnosis (1)		Nov 20, 2023	RCV006253682.1
Diffuse midline glioma, H3 K27M-mutant	Tier I (Strong) - diagnostic - supports diagnosis (1)		Feb 3, 2023	RCV006253686.1
Rosette-forming glioneuronal tumor	Tier I (Strong) - diagnostic - supports diagnosis (1)		Jan 2, 2024	RCV006253684.1
Vascular malformation	Tier I (Strong) - diagnostic - supports diagnosis (1)		Oct 7, 2025	RCV006253685.1

Submissions - Somatic

Clinical impact Help The submitted somatic clinical impact 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.

Tier I (Strong) - Diagnostic - supports diagnosis (Feb 03, 2023) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Diffuse midline glioma, H3 K27M-mutant	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104440.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (8) PubMed: 15647370‚ 15930273‚ 16432179‚ 24705251‚ 25219808‚ 28912153‚ 28966033‚ 29763623 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 28966033, 24705251, 29763623, 28912153, 25219808). (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

Tier I (Strong) - Diagnostic - supports diagnosis (Jan 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Rosette-forming glioneuronal tumor	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104458.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (10) PubMed: 15647370‚ 15930273‚ 16432179‚ 21997360‚ 23547894‚ 24806303‚ 27893178‚ 28912153‚ 31250151‚ 32859279 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in rosette-forming glioneuronal tumor of fourth ventricule, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 31250151, 32859279, 21997360, 23547894, 24806303, 27893178, 28912153). (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

Tier I (Strong) - Diagnostic - supports diagnosis (Mar 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Glioma	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104504.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (6) PubMed: 15647370‚ 15930273‚ 16432179‚ 28912153‚ 32289278‚ 35332262 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in glioma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 32289278, 28912153, 35332262). (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

Tier I (Strong) - Diagnostic - supports diagnosis (Oct 07, 2025) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Vascular malformation	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104760.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (6) PubMed: 16432179‚ 17376864‚ 25681199‚ 26627007‚ 29217067‚ 31536475 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in vascular malformation, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 26627007, 16432179, 17376864). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 25681199, 29217067, 31536475). (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

Tier II (Potential) - Diagnostic - supports diagnosis (Nov 20, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Alveolar rhabdomyosarcoma	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104455.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (7) PubMed: 15647370‚ 15930273‚ 16432179‚ 24332040‚ 24436047‚ 25768946‚ 34166060 Comment: show Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in alveolar rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 15647370, 15930273, 16432179). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 24436047, 34166060, 24332040, 25768946). (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

Tier II (Potential) - Diagnostic - supports diagnosis (Nov 30, 2025) N Not contributing to aggregate classification	no assertion criteria provided	Cervical squamous cell carcinoma	The Xing Lab, The Johns Hopkins University School of Medicine Accession: SCV007346397.1 First In ClinVar: Feb 07, 2026 Last updated: Feb 07, 2026	Publications: PubMed (6) PubMed: 18268322‚ 28112728‚ 29892689‚ 32653099‚ 35568000‚ 39717717 Comment: show Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in cervical squamous cell carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 18268322; 39717717). 3) Diagnostic significance for this tumor based on multiple studies (Evidence Level C; PMIDs: 28112728; 29892689; 32653099; 35568000). (less) Observation: 1 Collection method: research Allele origin: somatic Affected status: yes more Observation 1 Collection method: research Allele origin: somatic Affected status: yes Number of individuals with the variant: 4 Test name: PCR Platform type: Sanger sequencing

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.

Oncogenic (Mar 04, 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: SCV005094532.2 First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025	Publications: PubMed (3) PubMed: 16533766‚ 26627007‚ 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
Oncogenic activation of PI K3 CA in cancers: Emerging targeted therapies in precision oncology.	Wang Y	Genes & diseases	2024	PMID: 39717717
High incidence of PI3K pathway gene mutations in South Indian cervical cancers.	Rose MM	Cancer genetics	2022	PMID: 35568000
Molecular landscape of pediatric type IDH wildtype, H3 wildtype hemispheric glioblastomas.	Hong L	Laboratory investigation; a journal of technical methods and pathology	2022	PMID: 35332262
Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.	Shern JF	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2021	PMID: 34166060
Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.	Lucas CG	Acta neuropathologica communications	2020	PMID: 32859279
PIK3CA mutation and CNV status and post-chemoradiotherapy survival in patients with cervical cancer.	Martell K	Gynecologic oncology	2020	PMID: 32653099
Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.	Ryall S	Cancer cell	2020	PMID: 32289278
Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations.	Zenner K	JCI insight	2019	PMID: 31536475
Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1.	Sievers P	Acta neuropathologica	2019	PMID: 31250151
Tumor molecular profiling of responders and non-responders following pembrolizumab monotherapy in chemotherapy resistant advanced cervical cancer.	Ngoi NYL	Gynecologic oncology reports	2018	PMID: 29892689
Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial.	Mackay A	Cancer cell	2018	PMID: 29763623
Systematic Functional Annotation of Somatic Mutations in Cancer.	Ng PK	Cancer cell	2018	PMID: 29533785
Etiology and Genetics of Congenital Vascular Lesions.	Queisser A	Otolaryngologic clinics of North America	2018	PMID: 29217067
Comprehensive genetic characterization of rosette-forming glioneuronal tumors: independent component analysis by tissue microdissection.	Kitamura Y	Brain pathology (Zurich, Switzerland)	2018	PMID: 27893178
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.	Mackay A	Cancer cell	2017	PMID: 28966033
Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.	Johnson A	The oncologist	2017	PMID: 28912153
Integrated genomic and molecular characterization of cervical cancer.	Cancer Genome Atlas Research Network	Nature	2017	PMID: 28112728
Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations.	Dogruluk T	Cancer research	2015	PMID: 26627007
Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations.	Dogruluk T	Cancer research	2015	PMID: 26627007
Clonality and evolutionary history of rhabdomyosarcoma.	Chen L	PLoS genetics	2015	PMID: 25768946
Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA.	Luks VL	The Journal of pediatrics	2015	PMID: 25681199
The genetic signatures of pediatric high-grade glioma: no longer a one-act play.	Diaz AK	Seminars in radiation oncology	2014	PMID: 25219808
FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle.	Gessi M	Journal of neuropathology and experimental neurology	2014	PMID: 24806303
The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.	Wu G	Nature genetics	2014	PMID: 24705251
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.	Shern JF	Cancer discovery	2014	PMID: 24436047
Targeting oxidative stress in embryonal rhabdomyosarcoma.	Chen X	Cancer cell	2013	PMID: 24332040
Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer.	Thommen F	Clinical neuropathology	2013	PMID: 23547894
Recurrent PIK3CA mutations in rosette-forming glioneuronal tumor.	Ellezam B	Acta neuropathologica	2012	PMID: 21997360
Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms.	Zhao L	Proceedings of the National Academy of Sciences of the United States of America	2008	PMID: 18268322
Rare cancer-specific mutations in PIK3CA show gain of function.	Gymnopoulos M	Proceedings of the National Academy of Sciences of the United States of America	2007	PMID: 17376864
PIK3CA mutations in head and neck squamous cell carcinoma.	Qiu W	Clinical cancer research : an official journal of the American Association for Cancer Research	2006	PMID: 16533766
Cancer-specific mutations in PIK3CA are oncogenic in vivo.	Bader AG	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 16432179
Functional analysis of PIK3CA gene mutations in human colorectal cancer.	Ikenoue T	Cancer research	2005	PMID: 15930273
Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic.	Kang S	Proceedings of the National Academy of Sciences of the United States of America	2005	PMID: 15647370
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Text-mined citations for rs121913273 ...

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