ClinVar Genomic variation as it relates to human health
NM_006218.4(PIK3CA):c.325GAA[1] (p.Glu110del)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006218.4(PIK3CA):c.325GAA[1] (p.Glu110del)
Variation ID: 995382 Accession: VCV000995382.17
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 3q26.32 3: 179199150-179199152 (GRCh38) [ NCBI UCSC ] 3: 178916938-178916940 (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 Jan 26, 2021 May 12, 2024 Feb 12, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006218.4:c.325GAA[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006209.2:p.Glu110del inframe deletion NM_006218.4:c.328_330delGAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000003.12:g.179199150GAA[1] NC_000003.11:g.178916938GAA[1] NG_012113.2:g.55628GAA[1] LRG_310:g.55628GAA[1] LRG_310t1:c.328_330del - Protein change
- E110del
- Other names
- NM_006218.4:c.328_330del
- Canonical SPDI
- NC_000003.12:179199149:GAAGAA:GAA
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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
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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 |
1239 | 1273 |
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
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
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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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Pathogenic (2) |
criteria provided, single submitter
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Sep 29, 2023 | RCV001289461.10 | |
Likely pathogenic (1) |
reviewed by expert panel
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Feb 12, 2022 | RCV001836980.10 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Nov 11, 2022 | RCV003447584.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 12, 2022 | RCV002254349.19 | |
Likely pathogenic (1) |
no assertion criteria provided
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Mar 19, 2024 | RCV004527420.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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Mar 19, 2024 | RCV004527421.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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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. |
More information
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. |
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Likely pathogenic
(Feb 12, 2022)
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reviewed by expert panel
Method: curation
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Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Brain Malformations Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001949971.2 First in ClinVar: Oct 02, 2021 Last updated: Feb 20, 2022 |
Comment:
The NM_006218.4:c.325_327del (p.Glu110del) variant is predicted to cause a change in the length of the PIK3CA protein due to an in-frame deletion of one amino … (more)
The NM_006218.4:c.325_327del (p.Glu110del) variant is predicted to cause a change in the length of the PIK3CA protein due to an in-frame deletion of one amino acid. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; This variant has been shown to increase phosphorylation significantly above controls using patient derived cell lines (PMID: 29985963), it was identified in an individual with macrodactyly, in an individual with Cloves syndrome, two individuals with clinical diagnoses of MCAP and in two tumors within the COSMIC database (PMIDs: 28151489, 28502725, 29174369). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMIDs: 28502725, 28151489). In summary, this variant meets the criteria to be classified as Likely 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: PM2_P, PS4, PS2_M; 7 points (VCEP specifications version 1; Approved: 1/31/2021) (less)
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Pathogenic
(Jan 12, 2022)
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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: SCV002525577.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
This deletion of three nucleotides results in the in-frame loss of a single codon representing a glutamic acid at codon 110. Codon 110 is a … (more)
This deletion of three nucleotides results in the in-frame loss of a single codon representing a glutamic acid at codon 110. Codon 110 is a highly conserved amino acid position located within a linker region adjacent to the regulatory p85/adaptor-binding domain of the PI3 kinase p110-alpha catalytic subunit (UniProt #P42336). This is a recurrent pathogenic variant. Several unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the PIK3CA p.Glu110del variant have previously been reported (PMID: 28151489 and others). (less)
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Likely pathogenic
(Nov 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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CLOVES syndrome
(Somatic mutation)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175378.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The PIK3CA c.328_330del variant is classified as Likely Pathogenic (PS4, PM2, PM4) This PIK3CA c.328_330del variant results in an inframe deletion in exon 2/21. The … (more)
The PIK3CA c.328_330del variant is classified as Likely Pathogenic (PS4, PM2, PM4) This PIK3CA c.328_330del variant results in an inframe deletion in exon 2/21. The variant has been reported in affected tissue in many patients with overgrowth syndrome (PMID:28151489, PMID:28502725, PMID:29174369) (PS4). This variant is absent from population databases (PM2). This variant is predicted to alter the length of the protein produced by this gene due to an Inframe deletion variant in a nonrepeat region (PM4). The variant has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 995382). It has not been reported in dbSNP or HGMD. (less)
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Pathogenic
(Sep 29, 2023)
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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: SCV004176922.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
A PIK3CA c.328_330del (p.Glu110del) variant was identified at an allelic fraction consistent with somatic origin. The PIK3CA c.328_330del (p.Glu110del) variant has been reported in multiple … (more)
A PIK3CA c.328_330del (p.Glu110del) variant was identified at an allelic fraction consistent with somatic origin. The PIK3CA c.328_330del (p.Glu110del) variant has been reported in multiple individuals affected with PROS disorders (Chang F et al., PMID: 28502725; Siegel DH et al., PMID: 29174369; Steiner JE et al., PMID: 29516089; Parker VER et al., PMID: 30270358; Keppler-Noreuil KM et al., PMID: 31490637; McNulty SN et al., PMID: 31585106). This variant has been reported in the ClinVar database as a pathogenic somatic variant by two submitters and as a likely pathogenic germline variant by an expert panel (ClinVar Variation ID: 995382). It has also been reported in multiple cases in the cancer database COSMIC (Cosmic Genomic Mutation ID: COSV55874554). The PIK3CA c.328_330del (p.Glu110del) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the linker region, amino acids 106-186, between the adaptor-binding and Ras domains of p110a, which are defined as critical functional domains (Burke JE et al., PMID: 22949682). It is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region. Functional studies show this variant to be activating, as demonstrated by increased transformation ability in two different cell lines (Ng PK et al., PMID: 29533785). 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.328_330del (p.Glu110del) variant is classified as pathogenic. (less)
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Uncertain significance
(Feb 01, 2018)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563799.11
First in ClinVar: Aug 23, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 21, 2020)
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no assertion criteria provided
Method: clinical testing
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PIK3CA related overgrowth spectrum
Affected status: yes
Allele origin:
somatic
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001474044.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely pathogenic
(Mar 19, 2024)
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no assertion criteria provided
Method: clinical testing
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Rare venous malformation
Affected status: yes
Allele origin:
somatic
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Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038934.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 19, 2024)
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no assertion criteria provided
Method: clinical testing
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CLOVES syndrome
Affected status: yes
Allele origin:
somatic
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Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038935.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 19, 2024)
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no assertion criteria provided
Method: clinical testing
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Angioosteohypertrophic syndrome
Affected status: yes
Allele origin:
somatic
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Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038936.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Number of individuals with the variant: 2
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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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Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K-AKT-mTOR signaling pathway. | Bourgon N | Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology | 2022 | PMID: 34170046 |
Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics. | Siegel DH | The Journal of investigative dermatology | 2018 | PMID: 29174369 |
Molecular Diagnosis of Mosaic Overgrowth Syndromes Using a Custom-Designed Next-Generation Sequencing Panel. | Chang F | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28502725 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2b370fcd-bc06-47f2-a814-364c3d9b15f5 | - | - | - | - |
Text-mined citations for rs1724343994 ...
HelpRecord last updated May 27, 2024
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.