ClinVar Genomic variation as it relates to human health
NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)
Variation ID: 376470 Accession: VCV000376470.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q26.32 3: 179210291 (GRCh38) [ NCBI UCSC ] 3: 178928079 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 8, 2017 May 3, 2025 Mar 10, 2025 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006218.4:c.1357G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006209.2:p.Glu453Lys missense NC_000003.12:g.179210291G>A NC_000003.11:g.178928079G>A NG_012113.2:g.66769G>A LRG_310:g.66769G>A LRG_310t1:c.1357G>A - Protein change
- E453K
- Other names
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- Canonical SPDI
- NC_000003.12:179210290:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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PIK3CA | No evidence available | No evidence available |
GRCh38 GRCh37 |
1404 | 1439 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785580.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2024 | RCV000991209.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV001526693.11 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001327961.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 14, 2022 | RCV001775789.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 14, 2021 | RCV001861479.15 | |
PIK3CA-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2022 | RCV002244865.10 |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 10, 2025 | RCV002472374.10 |
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
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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. |
More information
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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. |
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Pathogenic
(Jun 25, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Megalencephaly-capillary malformation-polymicrogyria syndrome
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001521015.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(-)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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CLOVES syndrome
Affected status: yes
Allele origin:
somatic
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737114.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(Feb 01, 2022)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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PIK3CA-related disorder
Affected status: yes
Allele origin:
de novo
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Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002515365.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 26, 2021)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
somatic
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Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV002525708.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
This variant has previously been reported in multiple unrelated individuals with a molecular diagnosis of PROS, including those with reported overgrowth and macrodactyly (PMID: 27631024, … (more)
This variant has previously been reported in multiple unrelated individuals with a molecular diagnosis of PROS, including those with reported overgrowth and macrodactyly (PMID: 27631024, PMID: 31263565). The p.Glu453Lys variant substitutes the glutamic acid at position 453 with lysine within the C2 phosphatidylinositol 3-kinase domain of the PIK3CA protein (UniProt P42336, aa# 330-487). This is a recurrent hotspot. PIK3CA variants associated with PROS overlap those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases) (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Capillary malformation (present) , Overgrowth (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Vasculitis in the skin (present) , Hemihypertrophy (present) , Congenital macrodactylia (present)
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Pathogenic
(Sep 02, 2022)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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None
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557944.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 24, 2022 |
Comment:
A suspected mosaic missense variant was identified, NM_006218.2(PIK3CA):c.1357G>A in exon 8 of the PIK3CA gene. This substitution is predicted to create a minor amino acid … (more)
A suspected mosaic missense variant was identified, NM_006218.2(PIK3CA):c.1357G>A in exon 8 of the PIK3CA gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to a lysine at position 453 of the protein; NP_006209.2(PIK3CA):p.(Glu453Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located within the C2 domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in patients with overgrowth disorders (Mirzaa, G. et al . (2016); Piacitelli, A. et al . (2018)). A different variant in the same codon resulting in an inframe deletion has also been shown to cause the same condition (Mirzaa, G. et al . (2016); Riviere, J-B. et al . (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
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Pathogenic
(Oct 14, 2022)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002013346.3
First in ClinVar: Nov 12, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: increased phosphorylation of AKT on serine 473 (Rudd et al., 2011); In silico analysis supports that this missense … (more)
Published functional studies demonstrate a damaging effect: increased phosphorylation of AKT on serine 473 (Rudd et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23352210, 29759595, 26619011, 21531001, 27834349, 27631024, 30063105, 27037860, 31263565, 21266528) (less)
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Pathogenic
(Jun 01, 2023)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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CLOVES syndrome
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV003928007.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
This variant has been identified by standard clinical testing. somatic mutation
Number of individuals with the variant: 1
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Pathogenic
(Jun 14, 2021)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002247469.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with PIK3CA-associated overgrowth conditions (PMID: 27631024, 27631024, 28151489, ClinVar). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376470). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 453 of the PIK3CA protein (p.Glu453Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. (less)
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Pathogenic
(Nov 26, 2024)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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PIK3CA-related overgrowth syndrome
Affected status: yes
Allele origin:
somatic
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Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005902172.1
First in ClinVar: Apr 07, 2025 Last updated: Apr 07, 2025 |
Comment:
A PIK3CA c.1357G>A (p.Glu453Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-Related … (more)
A PIK3CA c.1357G>A (p.Glu453Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Mirzaa G et al., PMID: 27631024; Kuentz P et al., PMID: 28151489; McNulty SN et al., PMID: 31585106; Tian W et al., PMID: 33054853; Debelenko L et al., PMID: 36775953; Mojarad BA et al., 2023). This variant has been reported in the ClinVar database as pathogenic in both a somatic and germline state (ClinVar Variation ID: 376470) and it has been reported in numerous cases in the cancer database COSMIC (ID: COSV55874585). This variant is absent from the general population (gnomAD v4.1.0), indicating it is not a common variant. The PIK3CA c.1357G>A (p.Glu453Lys) variant resides within the C2 domain of PIK3CA and is defined as a critical functional domain (Lai et al, PMID: 35997716). 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 et al, PMID: 35997716). Functional studies show that this variant leads to increased AKT phosphorylation on Ser473, indicating that this variant is activating, and thereby promotes increased proliferation of cancer-derived cells in tissue culture (Rudd ML et al., PMID: 21266528; Smit DJ et al., PMID: 38909932). 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.1357G>A (p.Glu453Lys) variant is classified as pathogenic. (less)
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Pathogenic
(May 06, 2019)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-capillary malformation-polymicrogyria syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Undiagnosed Diseases Network, NIH
Accession: SCV001142587.2
First in ClinVar: Jan 12, 2020 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Clinical Features:
Polymicrogyria (present) , Plagiocephaly (present) , Macrocephaly at birth (present) , Macrocephalus (present) , Large for gestational age (present) , Hemimegalencephaly (present) , Hemihypertrophy (present) , Hemangioma (present) , Generalized hypotonia (present) , Cryptorchidism (present) , Capillary malformation (present)
Zygosity: Single Heterozygote
Age: 0-9 years
Sex: male
Ethnicity/Population group: White
Tissue: fibroblasts
Number of individuals demonstrating mosaicism for the variant: 1
Testing laboratory: Baylor Genetics
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Pathogenic
(Jul 10, 2024)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-capillary malformation-polymicrogyria syndrome
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV005395938.2
First in ClinVar: Nov 17, 2024 Last updated: Apr 28, 2025 |
Comment:
This variant was reported in multiple patients with PIK3CA-associated overgrowth condition (OMIM #602501, PMID 30063105, 22729224). This variant is not present in population database gnomAD … (more)
This variant was reported in multiple patients with PIK3CA-associated overgrowth condition (OMIM #602501, PMID 30063105, 22729224). This variant is not present in population database gnomAD (v4.1.0). It has been reported as pathogenic or likely pathogenic in ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 10, 2025)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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PIK3CA related overgrowth syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV006072195.1
First in ClinVar: May 03, 2025 Last updated: May 03, 2025 |
Comment:
Variant summary: PIK3CA c.1357G>A (p.Glu453Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: PIK3CA c.1357G>A (p.Glu453Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 228320 control chromosomes (gnomAD). c.1357G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth (Mirzaa_2016, Kuentz_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected the PIK3CA protein function (Burke_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22949682, 27631024, 28151489). ClinVar contains an entry for this variant (Variation ID: 376470). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 01, 2018)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: research
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Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000924154.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Platform type: next-gen sequencing
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Pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: provider interpretation
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Abnormal cardiovascular system morphology
Affected status: yes
Allele origin:
somatic
|
MAGI's Lab - Research, MAGI Group
Accession: SCV001437637.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. | Belanger Deloge R | European journal of human genetics : EJHG | 2023 | PMID: 36474027 |
Characterization of a severe case of PIK3CA-related overgrowth at autopsy by droplet digital polymerase chain reaction and report of PIK3CA sequencing in 22 patients. | Piacitelli AM | American journal of medical genetics. Part A | 2018 | PMID: 30063105 |
Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing. | Kuentz P | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28151489 |
PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. | Mirzaa G | JCI insight | 2016 | PMID: 27631024 |
Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA). | Burke JE | Proceedings of the National Academy of Sciences of the United States of America | 2012 | PMID: 22949682 |
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 |
Text-mined citations for rs1057519925 ...
HelpRecord last updated May 25, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.