A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are associated with PIK3CA-Related Overgrowth Spectrum (PROS) and the PIK3CA c.1633G>A; p.(Glu545Lys) (Chr3:g.178936091G>A) variant has previously been reported in patients with PROS, CLOVES syndrome, fibroadipose hyperplasia and isolated macrodactyly (PMID: 28151489, 29661094) The PIK3CA c.1633G>A; p.(Glu545Lys) variant results in a p110 alpha-helical domain substitution (PMID:26637981), activates AKT, disrupts normal EC-characteristic monolayer morphology as visualized by phase-contrast microscopy, results in loss of ECM fibronectin, and strongly downregulates ANGPT2 and PDGF-B mRNA expression as measured by real-time quantitative PCR. Plasminogen system-components are also somewhat dysregulated by the variant PIK3CA c.1633G>A; p.(Glu545Lys) (PMID:26637981). The variant is located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation: using strength Strong because Hot-spot of length 17 amino-acids has 21 non-VUS missense/in-frame variants (21 pathogenic and 0 benign), pathogenicity = 100.0%, qualifies as a dense hot-spot. The variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium: GnomAD exomes allele count = 1 is less than 5 for gene PIK3CA (good gnomAD exomes coverage = 42.7) and the variant is not found in gnomAD genomes (good gnomAD genomes coverage = 31.4). The variant is a missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before: alternative variants chr3:178936091G>C (Glu545Gln); chr3:178936092A>C (Glu545Ala); chr3:178936092A>G (Glu545Gly); chr3:178936092A>T (Glu545Val); chr3:178936093G>C (Glu545Asp) and chr3:178936093G>T (Glu545Asp) are classified Pathogenic. The variant is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease: 246 out of 254 non-VUS missense variants in gene PIK3CA are pathogenic = 96.9% which is more than threshold of 51.0%, and 259 out of 587 clinically reported variants in gene PIK3CA are pathogenic = 44.1% which is more than threshold of 12.0%. Multiple lines of computational evidence support a deleterious effect on the gene or gene product: Pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (PMID:30376034). The variant is annotated in Clinvar as a pathogenic variant associated with PIK3CA-related overgrowth spectrum (https://www.ncbi.nlm.nih.gov/clinvar/variation/13655/). Based on a modification of the ACMG Guidelines (PMID:25741868, 25880439), the PIK3CA c.1633G>A; p.(Glu545Lys) variant is classified as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_006218.4(PIK3CA):c.1633G>A (p.Glu545Lys)
Germline
Classification
Help
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.
(53)
Help
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.
Pathogenic/Likely pathogenic
53
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
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.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.
Oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_006218.4(PIK3CA):c.1633G>A (p.Glu545Lys)
Variation ID: 13655 Accession: VCV000013655.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q26.32 3: 179218303 (GRCh38) [ NCBI UCSC ] 3: 178936091 (GRCh37) [ NCBI UCSC ] 3: 180418785 (NCBI36) [ 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 Oct 20, 2024 Jan 1, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006218.4:c.1633G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006209.2:p.Glu545Lys missense NC_000003.12:g.179218303G>A NC_000003.11:g.178936091G>A NG_012113.2:g.74781G>A LRG_310:g.74781G>A LRG_310t1:c.1633G>A P42336:p.Glu545Lys - Protein change
- E545K
- Other names
- -
- Canonical SPDI
- NC_000003.12:179218302:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
gain_of_function_variant; Sequence Ontology [ SO:0002053]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
1303 | 1337 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014632.15 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014633.12 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014636.15 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014631.15 | |
| Pathogenic (3) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000038671.23 | |
| Pathogenic (2) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000055930.18 | |
| not provided (1) |
no classification provided
|
- | RCV000119356.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000417835.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000420851.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000423327.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000427202.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000428639.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000429391.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000431416.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432636.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000418058.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000433152.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000440053.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000425490.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000437876.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000438060.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000438587.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000441949.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000442569.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000421583.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000421958.8 | |
| Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000422210.11 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000426520.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000433976.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000438445.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000440694.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000441866.8 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV001092440.32 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2019 | RCV001262721.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2023 | RCV001290591.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001327963.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 30, 2020 | RCV001374447.8 | |
|
Cerebrofacial Vascular Metameric Syndrome (CVMS)
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 30, 2021 | RCV001730473.8 |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 21, 2021 | RCV001786329.8 | |
|
Segmental undergrowth associated with lymphatic malformation
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 6, 2021 | RCV001705591.8 |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV002508125.11 | |
|
PIK3CA overgrowth syndrome
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 9, 2020 | RCV004698419.1 |
| Likely pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2024 | RCV004527293.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2024 | RCV004527294.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2024 | RCV004527295.1 | |
|
HEMIFACIAL MYOHYPERPLASIA, SOMATIC
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV003764575.2 |
| click to load more click to collapse | ||||
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. |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Segmental undergrowth associated with lymphatic malformation
Affected status: yes
Allele origin:
somatic
|
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz
Accession: SCV001934208.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Limb undergrowth (present) , Lymphangioma (present)
|
|
|
Pathogenic
(Oct 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Eccrine Angiomatous Hamartoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Genomics For Life
Accession: SCV002028353.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
Comment:
A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are … (more)
A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are associated with PIK3CA-Related Overgrowth Spectrum (PROS) and the PIK3CA c.1633G>A; p.(Glu545Lys) (Chr3:g.178936091G>A) variant has previously been reported in patients with PROS, CLOVES syndrome, fibroadipose hyperplasia and isolated macrodactyly (PMID: 28151489, 29661094) The PIK3CA c.1633G>A; p.(Glu545Lys) variant results in a p110 alpha-helical domain substitution (PMID:26637981), activates AKT, disrupts normal EC-characteristic monolayer morphology as visualized by phase-contrast microscopy, results in loss of ECM fibronectin, and strongly downregulates ANGPT2 and PDGF-B mRNA expression as measured by real-time quantitative PCR. Plasminogen system-components are also somewhat dysregulated by the variant PIK3CA c.1633G>A; p.(Glu545Lys) (PMID:26637981). The variant is located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation: using strength Strong because Hot-spot of length 17 amino-acids has 21 non-VUS missense/in-frame variants (21 pathogenic and 0 benign), pathogenicity = 100.0%, qualifies as a dense hot-spot. The variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium: GnomAD exomes allele count = 1 is less than 5 for gene PIK3CA (good gnomAD exomes coverage = 42.7) and the variant is not found in gnomAD genomes (good gnomAD genomes coverage = 31.4). The variant is a missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before: alternative variants chr3:178936091G>C (Glu545Gln); chr3:178936092A>C (Glu545Ala); chr3:178936092A>G (Glu545Gly); chr3:178936092A>T (Glu545Val); chr3:178936093G>C (Glu545Asp) and chr3:178936093G>T (Glu545Asp) are classified Pathogenic. The variant is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease: 246 out of 254 non-VUS missense variants in gene PIK3CA are pathogenic = 96.9% which is more than threshold of 51.0%, and 259 out of 587 clinically reported variants in gene PIK3CA are pathogenic = 44.1% which is more than threshold of 12.0%. Multiple lines of computational evidence support a deleterious effect on the gene or gene product: Pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (PMID:30376034). The variant is annotated in Clinvar as a pathogenic variant associated with PIK3CA-related overgrowth spectrum (https://www.ncbi.nlm.nih.gov/clinvar/variation/13655/). Based on a modification of the ACMG Guidelines (PMID:25741868, 25880439), the PIK3CA c.1633G>A; p.(Glu545Lys) variant is classified as a pathogenic variant. (less)
Observation 1:
Clinical Features:
Eccrine Angiomatous Hamartoma (present)
Age: 20-29 years
Sex: female
Observation 2:
Clinical Features:
Eccrine Angiomatous Hamartoma (present)
Age: 10-19 years
Sex: male
|
|
|
Pathogenic
(Jan 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001772130.2
First in ClinVar: Aug 07, 2021 Last updated: Jun 10, 2023 |
Comment:
Published functional studies demonstrate a damaging effect, as E545K causes constitutive AKT phosphorylation and increases lipid kinase activity compared to wildtype (Ikenoue et al., 2005; … (more)
Published functional studies demonstrate a damaging effect, as E545K causes constitutive AKT phosphorylation and increases lipid kinase activity compared to wildtype (Ikenoue et al., 2005; Limaye et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15950905, 24080956, 29152088, 27317099, 25599672, 22729223, 23946963, 17376864, 16432179, 26637981, 27631024, 28425981, 30341384, 30547809, 32901329, 15930273, 22729224) (less)
|
|
|
Pathogenic
(Dec 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
PIK3CA overgrowth syndrome
Affected status: yes
Allele origin:
somatic
|
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV002525703.2
First in ClinVar: Jun 11, 2022 Last updated: Sep 01, 2024 |
Comment:
This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963, NBK153722 and others). The … (more)
This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963, NBK153722 and others). The p.E545K variant substitutes the glutamic acid at position 545 with lysine within the helical domain of the PIK3CA protein. 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 1:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Neoplasm (present)
Observation 7:
Number of individuals with the variant: 1
Clinical Features:
Vascular skin abnormality (present)
Observation 8:
Number of individuals with the variant: 1
Clinical Features:
Linear nevus sebaceous syndrome (present) , Intellectual disability (present) , Frontal polymicrogyria (present) , Seizure (present)
Observation 9:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 10:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 11:
Number of individuals with the variant: 1
Clinical Features:
Vascular skin abnormality (present) , Overgrowth (present)
Observation 12:
Number of individuals with the variant: 1
Clinical Features:
Hemihypertrophy of lower limb (present) , Abnormal vascular morphology (present)
Observation 13:
Number of individuals with the variant: 1
Clinical Features:
Vascular skin abnormality (present)
Observation 14:
Number of individuals with the variant: 1
Observation 15:
Number of individuals with the variant: 1
Observation 16:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
CLOVES syndrome
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440692.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
|
|
Pathogenic
(Jan 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PIK3CA related overgrowth syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001478679.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
Comment:
Variant summary: PIK3CA c.1633G>A (p.Glu545Lys) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, accessory (PIK) domain (IPR001263) of the encoded protein … (more)
Variant summary: PIK3CA c.1633G>A (p.Glu545Lys) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, accessory (PIK) domain (IPR001263) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247990 control chromosomes (gnomAD). c.1633G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth spectrum disorders (example: Baptiste-Riviere_2013, DGama_2016, Kuentz_2017, Mirzaa_2016, Yates_2018). In several of these patients, the variant was described as a mosaic mutation. In addition, somatic occurrence of this variant was also reported in a number tumors including but not limited to Breast Cancer and Seborrheic Keratosis (example: Hafner_2010, Juric_2019). These data indicate that the variant is very likely to be associated with disease. Several reports suggest that this variant is a hot-spot mutation. Consistent with these reports in functional studies, the variant was found to have greater lipid kinase activities. In vitro cell line studies expressing the variant also demonstrate constitutive activation of downstream components of PI3K signaling pathway. In transformation assays using NIH 3T3 cells, the variant induced more foci than the wild-type (Ikenoue_2005). Several ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic in the context of germline and somatic origin. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
CLOVES syndrome
Affected status: yes
Allele origin:
somatic
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737090.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
|
Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PIK3CA-related overgrowth syndrome
Affected status: yes
Allele origin:
somatic
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV004176947.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The PIK3CA c.1633G>A (p.Glu545Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with … (more)
The PIK3CA c.1633G>A (p.Glu545Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Mirzaa G et al., PMID: 27631024; Keppler-Noreuil KM et al., PMID: 25557259; Keppler-Noreuil KM et al., PMID: 24782230; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199; Jansen LA et al., PMID: 25722288; Piacitelli AM et al., PMID: 30063105). It has been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55873239), and it has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters in both a germline and somatic state (ClinVar ID: 13655). Another variant in the same codon, PIK3CA c.1634A>C (p.Glu545Ala), has been reported in individuals with lymphatic malformation and is considered pathogenic (Osborn AJ et al., PMID: 25292196; ClinVar ID: 13659). The PIK3CA c.1633G>A (p.Glu545Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. 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; Keppler-Noreuil KM et al., PMID: 25557259; Gymnopoulos M et al., PMID: 17376864). Computational predictors indicate that the PIK3CA c.1633G>A (p.Glu545Lys) variant is damaging, evidence that correlates with impact on PIK3CA function. In support of this prediction, functional in vitro and patient-derived cell studies show that this lysine substitution at codon 545 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling (Gymnopoulos M et al., PMID: 17376864; Menteş M et al. PMID: 35842959). Additionally, the PIK3CA gene is defined by the ClinGen Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID:35997716). 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.1633G>A (p.Glu545Lys) variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248954.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
PIK3CA: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP4
Number of individuals with the variant: 4
|
|
|
Pathogenic
(May 29, 2009)
|
no assertion criteria provided
Method: clinical testing
|
Non-Small Cell Lung Cancer
Affected status: not provided
Allele origin:
somatic
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062349.2
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 13
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
COLORECTAL CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000034888.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. (less)
|
|
|
Pathogenic
(Sep 30, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Cerebrofacial Vascular Metameric Syndrome (CVMS)
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
James Bennett Lab, Seattle Childrens Research Institute
Accession: SCV001960167.1
First in ClinVar: Oct 21, 2021 Last updated: Oct 21, 2021 |
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
BREAST CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000034886.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
OVARIAN CANCER, EPITHELIAL, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000034887.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
GASTRIC CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000034889.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
HEMIFACIAL MYOHYPERPLASIA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV004697481.2
First in ClinVar: Mar 05, 2024 Last updated: Mar 10, 2024 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
NONSMALL CELL LUNG CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000034890.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
KERATOSIS, SEBORRHEIC, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000034891.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
|
no assertion criteria provided
Method: literature only
|
MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000056678.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et … (more)
In 9 breast tumors (114480), 1 epithelial ovarian tumor (167000), and 2 colorectal tumors (114500) from a series of 284 primary human tumors, Campbell et al. (2004) identified a 1633G-A transition in exon 9 of the PIK3CA gene, resulting in a glu545-to-lys (E545K) substitution. Lee et al. (2005) identified the E545K mutation in tumor tissue from 2 breast cancers, 3 gastric cancers (137215), and 1 nonsmall cell lung cancer (211980). Hafner et al. (2007) identified a heterozygous somatic E545K mutation in 2 seborrheic keratosis lesions (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. In an individual with megalencephaly-capillary-malformation-polymicrogyria syndrome (MCAP; 602501), Riviere et al. (2012) identified the mosaic E545K mutation in the PIK3CA gene. Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 patients with hemimegalencephaly (HME) and identified the E545K missense mutation in the PIK3CA gene. The mutant allele was absent in blood but present in the brain, with a mutation burden of 36.6%. Lee et al. (2012) screened for this mutation in 15 other patients with HME and identified the E545K variant in 3, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot. In 2 patients (patients 1 and 5) with hemifacial myohyperplasia (HFMH; 606773), Bayard et al. (2023) identified mosaicism for the E545K mutation in the PIK3CA gene. Genotyping on muscle biopsies from affected regions found a mutation burden of 15% in patient 1 and 14% in patient 5. (less)
|
|
|
Pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503935.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503934.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Oct 02, 2014)
|
no assertion criteria provided
Method: literature only
|
Non-small cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503938.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503936.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Oct 02, 2014)
|
no assertion criteria provided
Method: literature only
|
Ovarian neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503937.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Brainstem glioma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503939.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Small cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503941.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Uterine carcinosarcoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503942.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Ovarian serous cystadenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503943.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant neoplasm of body of uterus
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503940.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Pancreatic adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503945.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Transitional cell carcinoma of the bladder
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503946.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Hepatocellular carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503947.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Gallbladder carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503944.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Nasopharyngeal neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503949.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Glioblastoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503950.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Prostate adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503951.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Squamous cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503948.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503953.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Renal cell carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503954.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant melanoma of skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503955.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of uterine cervix
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503952.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Carcinoma of esophagus
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503957.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Papillary renal cell carcinoma, sporadic
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503958.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of brain
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503959.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Gastric adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000503956.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(Dec 01, 2018)
|
no assertion criteria provided
Method: research
|
Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000924160.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: provider interpretation
|
Abnormal cardiovascular system morphology
Affected status: yes
Allele origin:
somatic
|
MAGI's Lab - Research, MAGI Group
Accession: SCV001437639.1
First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021 |
Observation 1: Observation 2: Observation 3: Observation 4: Observation 5: |
|
|
Pathogenic
(Oct 30, 2020)
|
no assertion criteria provided
Method: research
|
Gallbladder cancer
Affected status: yes
Allele origin:
somatic
|
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001571411.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
|
|
|
Likely pathogenic
(Mar 19, 2024)
|
no assertion criteria provided
Method: clinical testing
|
Rare venous malformation
Affected status: yes
Allele origin:
somatic
|
Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038940.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Mar 19, 2024)
|
no assertion criteria provided
Method: clinical testing
|
Rare combined vascular malformation
Affected status: yes
Allele origin:
somatic
|
Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038941.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Mar 19, 2024)
|
no assertion criteria provided
Method: clinical testing
|
Angioosteohypertrophic syndrome
Affected status: yes
Allele origin:
somatic
|
Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038942.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Number of individuals with the variant: 2
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
somatic
|
Laboratory of Translational Genomics, National Cancer Institute
Accession: SCV000154253.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Pediatric sarcoma specimen
|
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Megalencephaly-capillary malformation-polymicrogyria syndrome
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000086943.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Published functional studies demonstrate a damaging effect, as E545K causes constitutive AKT phosphorylation and increases lipid kinase activity compared to wildtype (Ikenoue et al., 2005; Limaye et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15950905, 24080956, 29152088, 27317099, 25599672, 22729223, 23946963, 17376864, 16432179, 26637981, 27631024, 28425981, 30341384, 30547809, 32901329, 15930273, 22729224)
Comment:
This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963, NBK153722 and others). The p.E545K variant substitutes the glutamic acid at position 545 with lysine within the helical domain of the PIK3CA protein. 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:
Variant summary: PIK3CA c.1633G>A (p.Glu545Lys) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, accessory (PIK) domain (IPR001263) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247990 control chromosomes (gnomAD). c.1633G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth spectrum disorders (example: Baptiste-Riviere_2013, DGama_2016, Kuentz_2017, Mirzaa_2016, Yates_2018). In several of these patients, the variant was described as a mosaic mutation. In addition, somatic occurrence of this variant was also reported in a number tumors including but not limited to Breast Cancer and Seborrheic Keratosis (example: Hafner_2010, Juric_2019). These data indicate that the variant is very likely to be associated with disease. Several reports suggest that this variant is a hot-spot mutation. Consistent with these reports in functional studies, the variant was found to have greater lipid kinase activities. In vitro cell line studies expressing the variant also demonstrate constitutive activation of downstream components of PI3K signaling pathway. In transformation assays using NIH 3T3 cells, the variant induced more foci than the wild-type (Ikenoue_2005). Several ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic in the context of germline and somatic origin. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The PIK3CA c.1633G>A (p.Glu545Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Mirzaa G et al., PMID: 27631024; Keppler-Noreuil KM et al., PMID: 25557259; Keppler-Noreuil KM et al., PMID: 24782230; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199; Jansen LA et al., PMID: 25722288; Piacitelli AM et al., PMID: 30063105). It has been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55873239), and it has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters in both a germline and somatic state (ClinVar ID: 13655). Another variant in the same codon, PIK3CA c.1634A>C (p.Glu545Ala), has been reported in individuals with lymphatic malformation and is considered pathogenic (Osborn AJ et al., PMID: 25292196; ClinVar ID: 13659). The PIK3CA c.1633G>A (p.Glu545Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. 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; Keppler-Noreuil KM et al., PMID: 25557259; Gymnopoulos M et al., PMID: 17376864). Computational predictors indicate that the PIK3CA c.1633G>A (p.Glu545Lys) variant is damaging, evidence that correlates with impact on PIK3CA function. In support of this prediction, functional in vitro and patient-derived cell studies show that this lysine substitution at codon 545 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling (Gymnopoulos M et al., PMID: 17376864; Menteş M et al. PMID: 35842959). Additionally, the PIK3CA gene is defined by the ClinGen Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID:35997716). 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.1633G>A (p.Glu545Lys) variant is classified as pathogenic.
Comment:
PIK3CA: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP4
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
gain_of_function_variant
|
James Bennett Lab, Seattle Childrens Research Institute
Accession: SCV001960167.1
|
|
Comment:
A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are associated with PIK3CA-Related Overgrowth Spectrum (PROS) and the PIK3CA c.1633G>A; p.(Glu545Lys) (Chr3:g.178936091G>A) variant has previously been reported in patients with PROS, CLOVES syndrome, fibroadipose hyperplasia and isolated macrodactyly (PMID: 28151489, 29661094) The PIK3CA c.1633G>A; p.(Glu545Lys) variant results in a p110 alpha-helical domain substitution (PMID:26637981), activates AKT, disrupts normal EC-characteristic monolayer morphology as visualized by phase-contrast microscopy, results in loss of ECM fibronectin, and strongly downregulates ANGPT2 and PDGF-B mRNA expression as measured by real-time quantitative PCR. Plasminogen system-components are also somewhat dysregulated by the variant PIK3CA c.1633G>A; p.(Glu545Lys) (PMID:26637981). The variant is located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation: using strength Strong because Hot-spot of length 17 amino-acids has 21 non-VUS missense/in-frame variants (21 pathogenic and 0 benign), pathogenicity = 100.0%, qualifies as a dense hot-spot. The variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium: GnomAD exomes allele count = 1 is less than 5 for gene PIK3CA (good gnomAD exomes coverage = 42.7) and the variant is not found in gnomAD genomes (good gnomAD genomes coverage = 31.4). The variant is a missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before: alternative variants chr3:178936091G>C (Glu545Gln); chr3:178936092A>C (Glu545Ala); chr3:178936092A>G (Glu545Gly); chr3:178936092A>T (Glu545Val); chr3:178936093G>C (Glu545Asp) and chr3:178936093G>T (Glu545Asp) are classified Pathogenic. The variant is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease: 246 out of 254 non-VUS missense variants in gene PIK3CA are pathogenic = 96.9% which is more than threshold of 51.0%, and 259 out of 587 clinically reported variants in gene PIK3CA are pathogenic = 44.1% which is more than threshold of 12.0%. Multiple lines of computational evidence support a deleterious effect on the gene or gene product: Pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (PMID:30376034). The variant is annotated in Clinvar as a pathogenic variant associated with PIK3CA-related overgrowth spectrum (https://www.ncbi.nlm.nih.gov/clinvar/variation/13655/). Based on a modification of the ACMG Guidelines (PMID:25741868, 25880439), the PIK3CA c.1633G>A; p.(Glu545Lys) variant is classified as a pathogenic variant.
Comment:
Published functional studies demonstrate a damaging effect, as E545K causes constitutive AKT phosphorylation and increases lipid kinase activity compared to wildtype (Ikenoue et al., 2005; Limaye et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15950905, 24080956, 29152088, 27317099, 25599672, 22729223, 23946963, 17376864, 16432179, 26637981, 27631024, 28425981, 30341384, 30547809, 32901329, 15930273, 22729224)
Comment:
This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963, NBK153722 and others). The p.E545K variant substitutes the glutamic acid at position 545 with lysine within the helical domain of the PIK3CA protein. 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:
Variant summary: PIK3CA c.1633G>A (p.Glu545Lys) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, accessory (PIK) domain (IPR001263) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247990 control chromosomes (gnomAD). c.1633G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth spectrum disorders (example: Baptiste-Riviere_2013, DGama_2016, Kuentz_2017, Mirzaa_2016, Yates_2018). In several of these patients, the variant was described as a mosaic mutation. In addition, somatic occurrence of this variant was also reported in a number tumors including but not limited to Breast Cancer and Seborrheic Keratosis (example: Hafner_2010, Juric_2019). These data indicate that the variant is very likely to be associated with disease. Several reports suggest that this variant is a hot-spot mutation. Consistent with these reports in functional studies, the variant was found to have greater lipid kinase activities. In vitro cell line studies expressing the variant also demonstrate constitutive activation of downstream components of PI3K signaling pathway. In transformation assays using NIH 3T3 cells, the variant induced more foci than the wild-type (Ikenoue_2005). Several ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic in the context of germline and somatic origin. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The PIK3CA c.1633G>A (p.Glu545Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Mirzaa G et al., PMID: 27631024; Keppler-Noreuil KM et al., PMID: 25557259; Keppler-Noreuil KM et al., PMID: 24782230; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199; Jansen LA et al., PMID: 25722288; Piacitelli AM et al., PMID: 30063105). It has been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55873239), and it has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters in both a germline and somatic state (ClinVar ID: 13655). Another variant in the same codon, PIK3CA c.1634A>C (p.Glu545Ala), has been reported in individuals with lymphatic malformation and is considered pathogenic (Osborn AJ et al., PMID: 25292196; ClinVar ID: 13659). The PIK3CA c.1633G>A (p.Glu545Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. 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; Keppler-Noreuil KM et al., PMID: 25557259; Gymnopoulos M et al., PMID: 17376864). Computational predictors indicate that the PIK3CA c.1633G>A (p.Glu545Lys) variant is damaging, evidence that correlates with impact on PIK3CA function. In support of this prediction, functional in vitro and patient-derived cell studies show that this lysine substitution at codon 545 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling (Gymnopoulos M et al., PMID: 17376864; Menteş M et al. PMID: 35842959). Additionally, the PIK3CA gene is defined by the ClinGen Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID:35997716). 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.1633G>A (p.Glu545Lys) variant is classified as pathogenic.
Comment:
PIK3CA: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP4
Citations for germline classification of this variant
Help| 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 |
| Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations. | Zenner K | JCI insight | 2019 | PMID: 31536475 |
| Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. | Juric D | JAMA oncology | 2019 | PMID: 30543347 |
| VarSome: the human genomic variant search engine. | Kopanos C | Bioinformatics (Oxford, England) | 2019 | PMID: 30376034 |
| An investigation of PIK3CA mutations in isolated macrodactyly. | Wu J | The Journal of hand surgery, European volume | 2018 | PMID: 29661094 |
| Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development. | Yates CL | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28425981 |
| 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 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| A classification system for clinical relevance of somatic variants identified in molecular profiling of cancer. | Sukhai MA | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25880439 |
| Somatic Activating PIK3CA Mutations Cause Venous Malformation. | Limaye N | American journal of human genetics | 2015 | PMID: 26637981 |
| Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. | Dogruluk T | Cancer research | 2015 | PMID: 26627007 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. | D'Gama AM | Annals of neurology | 2015 | PMID: 25599672 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. | Beaver JA | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23888070 |
| PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. | Janku F | Cancer research | 2013 | PMID: 23066039 |
| 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 |
| De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. | Lee JH | Nature genetics | 2012 | PMID: 22729223 |
| Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. | Kurek KC | American journal of human genetics | 2012 | PMID: 22658544 |
| PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. | Janku F | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22271473 |
| Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. | Bendell JC | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22162589 |
| Phosphatidylinositide-3-kinase inhibitors: addressing questions of isoform selectivity and pharmacodynamic/predictive biomarkers in early clinical trials. | Clarke PA | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22162582 |
| Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. | Sequist LV | Science translational medicine | 2011 | PMID: 21430269 |
| Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors. | Hafner C | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 21078999 |
| Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. | De Roock W | The Lancet. Oncology | 2010 | PMID: 20619739 |
| Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. | O'Brien C | Clinical cancer research : an official journal of the American Association for Cancer Research | 2010 | PMID: 20453058 |
| PIK3CA mutations predict local recurrences in rectal cancer patients. | He Y | Clinical cancer research : an official journal of the American Association for Cancer Research | 2009 | PMID: 19903786 |
| A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells. | Zou ZQ | International journal of molecular medicine | 2009 | PMID: 19513541 |
| PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. | Prenen H | Clinical cancer research : an official journal of the American Association for Cancer Research | 2009 | PMID: 19366826 |
| PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. | Sartore-Bianchi A | Cancer research | 2009 | PMID: 19223544 |
| Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. | Engelman JA | Nature medicine | 2008 | PMID: 19029981 |
| Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. | She QB | PloS one | 2008 | PMID: 18725974 |
| An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. | Stemke-Hale K | Cancer research | 2008 | PMID: 18676830 |
| Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. | Hafner C | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17673550 |
| PIK3CA mutation status in Japanese lung cancer patients. | Kawano O | Lung cancer (Amsterdam, Netherlands) | 2006 | PMID: 16930767 |
| Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. | Engelman JA | The Journal of clinical investigation | 2006 | PMID: 16906227 |
| Functional analysis of PIK3CA gene mutations in human colorectal cancer. | Ikenoue T | Cancer research | 2005 | PMID: 15930273 |
| PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. | Saal LH | Cancer research | 2005 | PMID: 15805248 |
| 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 |
| PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. | Lee JW | Oncogene | 2005 | PMID: 15608678 |
| Mutation of the PIK3CA gene in ovarian and breast cancer. | Campbell IG | Cancer research | 2004 | PMID: 15520168 |
| The PIK3CA gene is mutated with high frequency in human breast cancers. | Bachman KE | Cancer biology & therapy | 2004 | PMID: 15254419 |
| High frequency of mutations of the PIK3CA gene in human cancers. | Samuels Y | Science (New York, N.Y.) | 2004 | PMID: 15016963 |
| http://docm.genome.wustl.edu/variants/ENST00000263967:c.1633G>A | - | - | - | - |
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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
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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
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The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
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The most recent date that a submitter evaluated this variant for the tumor type. |
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Oncogenic
criteria provided, single submitter
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Jul 31, 2024 | RCV004668729.1 |
Submissions - Somatic
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Oncogenicity
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The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
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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
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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
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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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Oncogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm
Affected status: unknown
Allele origin:
somatic
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094533.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
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Comment:
A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are associated with PIK3CA-Related Overgrowth Spectrum (PROS) and the PIK3CA c.1633G>A; p.(Glu545Lys) (Chr3:g.178936091G>A) variant has previously been reported in patients with PROS, CLOVES syndrome, fibroadipose hyperplasia and isolated macrodactyly (PMID: 28151489, 29661094) The PIK3CA c.1633G>A; p.(Glu545Lys) variant results in a p110 alpha-helical domain substitution (PMID:26637981), activates AKT, disrupts normal EC-characteristic monolayer morphology as visualized by phase-contrast microscopy, results in loss of ECM fibronectin, and strongly downregulates ANGPT2 and PDGF-B mRNA expression as measured by real-time quantitative PCR. Plasminogen system-components are also somewhat dysregulated by the variant PIK3CA c.1633G>A; p.(Glu545Lys) (PMID:26637981). The variant is located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation: using strength Strong because Hot-spot of length 17 amino-acids has 21 non-VUS missense/in-frame variants (21 pathogenic and 0 benign), pathogenicity = 100.0%, qualifies as a dense hot-spot. The variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium: GnomAD exomes allele count = 1 is less than 5 for gene PIK3CA (good gnomAD exomes coverage = 42.7) and the variant is not found in gnomAD genomes (good gnomAD genomes coverage = 31.4). The variant is a missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before: alternative variants chr3:178936091G>C (Glu545Gln); chr3:178936092A>C (Glu545Ala); chr3:178936092A>G (Glu545Gly); chr3:178936092A>T (Glu545Val); chr3:178936093G>C (Glu545Asp) and chr3:178936093G>T (Glu545Asp) are classified Pathogenic. The variant is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease: 246 out of 254 non-VUS missense variants in gene PIK3CA are pathogenic = 96.9% which is more than threshold of 51.0%, and 259 out of 587 clinically reported variants in gene PIK3CA are pathogenic = 44.1% which is more than threshold of 12.0%. Multiple lines of computational evidence support a deleterious effect on the gene or gene product: Pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (PMID:30376034). The variant is annotated in Clinvar as a pathogenic variant associated with PIK3CA-related overgrowth spectrum (https://www.ncbi.nlm.nih.gov/clinvar/variation/13655/). Based on a modification of the ACMG Guidelines (PMID:25741868, 25880439), the PIK3CA c.1633G>A; p.(Glu545Lys) variant is classified as a pathogenic variant.
Comment:
Published functional studies demonstrate a damaging effect, as E545K causes constitutive AKT phosphorylation and increases lipid kinase activity compared to wildtype (Ikenoue et al., 2005; Limaye et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15950905, 24080956, 29152088, 27317099, 25599672, 22729223, 23946963, 17376864, 16432179, 26637981, 27631024, 28425981, 30341384, 30547809, 32901329, 15930273, 22729224)
Comment:
This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963, NBK153722 and others). The p.E545K variant substitutes the glutamic acid at position 545 with lysine within the helical domain of the PIK3CA protein. 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:
Variant summary: PIK3CA c.1633G>A (p.Glu545Lys) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, accessory (PIK) domain (IPR001263) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247990 control chromosomes (gnomAD). c.1633G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth spectrum disorders (example: Baptiste-Riviere_2013, DGama_2016, Kuentz_2017, Mirzaa_2016, Yates_2018). In several of these patients, the variant was described as a mosaic mutation. In addition, somatic occurrence of this variant was also reported in a number tumors including but not limited to Breast Cancer and Seborrheic Keratosis (example: Hafner_2010, Juric_2019). These data indicate that the variant is very likely to be associated with disease. Several reports suggest that this variant is a hot-spot mutation. Consistent with these reports in functional studies, the variant was found to have greater lipid kinase activities. In vitro cell line studies expressing the variant also demonstrate constitutive activation of downstream components of PI3K signaling pathway. In transformation assays using NIH 3T3 cells, the variant induced more foci than the wild-type (Ikenoue_2005). Several ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic in the context of germline and somatic origin. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The PIK3CA c.1633G>A (p.Glu545Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Mirzaa G et al., PMID: 27631024; Keppler-Noreuil KM et al., PMID: 25557259; Keppler-Noreuil KM et al., PMID: 24782230; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199; Jansen LA et al., PMID: 25722288; Piacitelli AM et al., PMID: 30063105). It has been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55873239), and it has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters in both a germline and somatic state (ClinVar ID: 13655). Another variant in the same codon, PIK3CA c.1634A>C (p.Glu545Ala), has been reported in individuals with lymphatic malformation and is considered pathogenic (Osborn AJ et al., PMID: 25292196; ClinVar ID: 13659). The PIK3CA c.1633G>A (p.Glu545Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. 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; Keppler-Noreuil KM et al., PMID: 25557259; Gymnopoulos M et al., PMID: 17376864). Computational predictors indicate that the PIK3CA c.1633G>A (p.Glu545Lys) variant is damaging, evidence that correlates with impact on PIK3CA function. In support of this prediction, functional in vitro and patient-derived cell studies show that this lysine substitution at codon 545 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling (Gymnopoulos M et al., PMID: 17376864; Menteş M et al. PMID: 35842959). Additionally, the PIK3CA gene is defined by the ClinGen Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID:35997716). 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.1633G>A (p.Glu545Lys) variant is classified as pathogenic.
Comment:
PIK3CA: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP4
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs104886003 ...
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Record last updated Nov 25, 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.