The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25424831). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021)
ClinVar Genomic variation as it relates to human health
NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Classification is based on the expert panel submission
Feb 2022 by
ClinGen Brain Malformations Variant Curation Expert Panel
Help
FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
Clinical impact
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
9 out of 11 submissions contributed to this classification
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
11
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Oncogenic
This classification is based on the single submission received
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
Variant Details
- Identifiers
-
NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg)
Variation ID: 13652 Accession: VCV000013652.100
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q26.32 3: 179234297 (GRCh38) [ NCBI UCSC ] 3: 178952085 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 1, 2013 Jan 11, 2026 Feb 11, 2022 Somatic - Clinical impact Nov 22, 2025 Nov 22, 2025 May 8, 2025 Somatic - Oncogenicity Aug 11, 2024 Jan 3, 2026 Dec 29, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006218.4:c.3140A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006209.2:p.His1047Arg missense NC_000003.12:g.179234297A>G NC_000003.11:g.178952085A>G NG_012113.2:g.90775A>G LRG_310:g.90775A>G LRG_310t1:c.3140A>G P42336:p.His1047Arg - Protein change
- H1047R
- Other names
-
NM_006218.4(PIK3CA):c.3140A>G
COSM775
- Canonical SPDI
- NC_000003.12:179234296:A:G
-
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.
- -
- 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 |
1567 | 1605 | |
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 | RCV000014623.18 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014624.17 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014626.18 | |
| Pathogenic (2) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014627.24 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014628.18 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000014622.18 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Nov 11, 2019 | RCV000024621.30 | |
| Pathogenic (2) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000154516.16 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Apr 19, 2019 | RCV000201231.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV000487449.13 | |
|
MACRODACTYLY, SOMATIC
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV000709691.12 |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV001092442.48 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 30, 2019 | RCV001255686.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001526648.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001327968.10 | |
|
Segmental undergrowth associated with mainly venous malformation with capillary component
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 6, 2021 | RCV001705589.10 |
|
Segmental undergrowth associated with lymphatic malformation
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 6, 2021 | RCV001705590.10 |
|
CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV001728091.10 |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 11, 2024 | RCV001729349.11 | |
|
Cerebrofacial Vascular Metameric Syndrome (CVMS)
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 30, 2021 | RCV001730472.11 |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 12, 2021 | RCV001807727.11 | |
| Pathogenic (1) |
reviewed by expert panel
|
Feb 11, 2022 | RCV001836707.12 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003128082.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2012 | RCV002508124.9 | |
|
Klippel-Trenaunay-like-Syndrome
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 23, 2023 | RCV003325939.7 |
| Likely pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2024 | RCV004527291.2 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2024 | RCV004527290.2 | |
|
PIK3CA-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Mar 27, 2024 | RCV004737153.2 |
|
PIK3CA-Related Overgrowth Spectrum Disorders
|
Pathogenic (1) |
criteria provided, single submitter
|
May 8, 2024 | RCV005051734.1 |
| click to load more conditions 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. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 11, 2022)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
(Autosomal dominant inheritance)
|
ClinGen Brain Malformations Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001949970.2 First in ClinVar: Oct 02, 2021 Last updated: Feb 20, 2022 |
Comment:
show
The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25424831). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021) (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 11, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
CLOVES syndrome |
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428754.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 01, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
CLAPO syndrome |
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976965.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Aug 05, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Not provided |
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061476.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Sep 20, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV002525705.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
show
This variant substitutes the histidine with arginine at position 1047 within the PIK3CA kinase domain. This is a recurrent pathogenic variant. Several unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the somatic activating PIK3CA p.His1047Arg variant have previously been reported (PMID: 25681199, PMID: 26637981, PMID: 24903541, PMID: 30180809, PMID: 28328134 and others). (less)
Observation:
18
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 2
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 3
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 4
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 5
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 6
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 7
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present) , Overgrowth (present)
Observation 8
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Venous malformation (present)
Observation 9
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Neoplasm (present) , Vascular skin abnormality (present) , Hemangioma (present)
Observation 10
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 11
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
Observation 12
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Congenital macrodactylia (present) , Macrodactyly of finger (present)
Observation 13
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Observation 14
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Observation 15
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Observation 16
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Observation 17
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Observation 18
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormal lymphatic vessel morphology (present)
|
|
|
Pathogenic
(Aug 03, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV002559314.2
First in ClinVar: Aug 15, 2022 Last updated: Mar 04, 2023 |
Comment:
show
Reported as a somatic variant in various tumor samples (Campbell et al., 2004; Li et al., 2005); Published functional studies demonstrate increased lipid kinase activity and transforming activities, and a mouse model with this variant demonstrated increased body weight, increased organ size, and severe metabolic defects (Ikenoue et al., 2005; Kinross et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16322209, 15289301, 15016963, 25599672, 23100325, 25550458, 15930273, 16432179, 19805105, 21708979, 15520168, 15784156, 27631024, 24903541, 22658544, 32770747, 34568242, 34075207) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 23, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Klippel-Trenaunay-like-Syndrome
|
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Accession: SCV003853395.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
CLOVES syndrome |
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005417439.2
First in ClinVar: Nov 30, 2024 Last updated: Oct 05, 2025 |
Comment:
show
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 11, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
CLAPO syndrome |
3billion
Accession: SCV006581619.1
First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025 |
Comment:
show
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.46 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.66 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013652 /PMID: 25599672). Different missense changes at the same codon (p.His1047Gln, p.His1047Leu, p.His1047Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013653, VCV000039705, VCV000376481 /PMID: 22729224, 28151489 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Method: exome sequencing
|
|
|
Pathogenic
(Aug 01, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248958.36
First in ClinVar: May 12, 2020 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 3
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
CLOVES syndrome |
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803841.1 First in ClinVar: Apr 21, 2017 Last updated: Apr 21, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Congenital macrodactylia |
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737079.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Pathogenic
(Apr 06, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Segmental undergrowth associated with lymphatic malformation
|
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz
Accession: SCV001934209.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 2
Clinical Features:
Limb undergrowth (present) , Lymphangioma (present)
Platform type: next-gen sequencing
|
|
|
Pathogenic
(Apr 06, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Segmental undergrowth associated with mainly venous malformation with capillary component
|
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz
Accession: SCV001934211.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Limb undergrowth (present) , Venous malformation (present) , Capillary malformation (present)
Platform type: next-gen sequencing
|
|
|
Pathogenic
(Feb 12, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Megalencephaly-capillary malformation-polymicrogyria syndrome |
CENTOGENE GmbH and LLC - Guiding Precision Medicine
Accession: SCV002059601.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: no
|
|
|
Likely pathogenic
(Nov 03, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009609.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
|
|
|
Pathogenic
(May 08, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
PIK3CA-Related Overgrowth Spectrum Disorders
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005685468.1
First in ClinVar: Feb 01, 2025 Last updated: Feb 01, 2025 |
Comment:
show
The PIK3CA c.3140A>G (p.His1047Arg) variant was identified. This variant has been reported in numerous individuals affected with PROS disorders (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; Mirzaa G et al., PMID: 27631024; Kurek KC et al, PMID: 22658544). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic both in a germline and a somatic state by numerous submitters, including an expert panel (ClinVar ID: 13652). It has also been reported in multiple cases in the cancer database COSMIC (COSMIC ID: COSV55873195). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The PIK3CA c.3140A>G (p.His1047Arg) variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain (Zhao L et al., PMID: 18268322; Samuels Y et al., PMID: 15016963; Lai A et al., PMID: 35997716). Functional studies showed autonomous activation and enhanced Akt-mTOR signaling in vitro and tumorigenesis in vivo, indicating that this variant impacts protein function (Yuan W et al., PMID: 22370636; Loconte DC et al., PMID: 25915946; Rios JJ et al., PMID: 23100325; Lindhurst MJ et al., PMID: 22729222; Tikoo A et al., PMID: 22666336). Other variants in the same codon, c.3140A>T (p.His1047Leu) and c.3139C>T (p.His1047Tyr), have been reported in individuals with PROS disorders and are considered pathogenic (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; ClinVar ID: 13653, 39705). The PIK3CA gene is defined by the ClinGen Brain Malformation Expert Panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (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.3140A>G (p.His1047Arg) variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rosette-forming glioneuronal tumor |
Donald Williams Parsons Laboratory, Baylor College of Medicine
Additional submitter:
Sharon E. Plon Laboratory, Baylor College of Medicine
Study: CSER-BASIC3
Accession: SCV000292259.3 First in ClinVar: Apr 28, 2017 Last updated: Apr 13, 2025
Comment:
The c.3140A>G missense mutation (p.H1047R) identified in exon 21 of PIK3CA is the most frequently-observed PIK3CA hotspot alteration in human cancers , including high grade … (more)
The c.3140A>G missense mutation (p.H1047R) identified in exon 21 of PIK3CA is the most frequently-observed PIK3CA hotspot alteration in human cancers , including high grade gliomas and glioneuronal tumors (Ellezam et al. 2012), and has also been demonstrated to result in constitutive activation of the PI3K/AKT/mTOR pathway (Bader et al. 2005, Engelman 2009, Thorpe et al. 2015, Wu et al. 2014) (less)
|
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Clinical Features:
Rosette-forming glioneuronal tumor (present)
Comment on clinical features:
negative for somatic alterations in BRAF (V600E point mutation and KIAA1549-BRAF fusion) and hotspot mutations in IDH1 and IDH2 by pyrosequencing
Zygosity: Single Heterozygote
Age: 10-19 years
Sex: female
Ethnicity/Population group: African American
Tissue: frozen tumor sample : Rosette-forming glioneuronal tumor of the fourth ventricle
Platform type: next-gen sequencing
Platform name: HiSeq
|
|
|
Pathogenic
(Oct 23, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided
(Autosomal unknown)
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446687.2
First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Overgrowth (present) , Congenital macrodactylia (present)
Sex: female
|
|
|
Pathogenic
(Apr 19, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
PIK3CA related overgrowth spectrum
(Somatic mutation)
|
Biesecker Lab Rare Disease, National Institutes of Health
Accession: SCV000898478.3
First in ClinVar: Apr 28, 2019 Last updated: Aug 03, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Clinical Features:
overgrowth (present)
Sex: male
Comment on evidence:
"effect on protein activity" was previously submitted as the functional consequence for NM_006218.3:c.3140A>G, but without providing the result of a functional assay.
|
|
|
Pathogenic
(Aug 05, 2010)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Non-Small Cell Lung Cancer |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000199905.1
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Number of individuals with the variant: 12
|
|
|
Pathogenic
(Aug 05, 2010)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ovarian Cancer |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204187.1
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 30, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Lip and oral cavity carcinoma |
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432251.1
First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020 |
Observation: 1
Collection method: research
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Abnormal cardiovascular system morphology |
MAGI's Lab - Research, MAGI Group
Accession: SCV001437644.1
First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021 |
Observation:
5
Observation 1
Collection method: provider interpretation
Allele origin: somatic
Affected status: yes
Observation 2
Collection method: provider interpretation
Allele origin: somatic
Affected status: yes
Observation 3
Collection method: provider interpretation
Allele origin: somatic
Affected status: yes
Observation 4
Collection method: provider interpretation
Allele origin: somatic
Affected status: yes
Observation 5
Collection method: provider interpretation
Allele origin: somatic
Affected status: yes
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
BREAST CANCER, SOMATIC |
OMIM
Accession: SCV000034877.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
OVARIAN CANCER, EPITHELIAL, SOMATIC |
OMIM
Accession: SCV000034878.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
COLORECTAL CANCER, SOMATIC |
OMIM
Accession: SCV000034879.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
GASTRIC CANCER, SOMATIC |
OMIM
Accession: SCV000034880.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
HEPATOCELLULAR CARCINOMA, SOMATIC |
OMIM
Accession: SCV000034881.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
NONSMALL CELL LUNG CANCER, SOMATIC |
OMIM
Accession: SCV000034882.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
KERATOSIS, SEBORRHEIC, SOMATIC |
OMIM
Accession: SCV000034883.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI, SOMATIC |
OMIM
Accession: SCV000050487.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
MACRODACTYLY, SOMATIC |
OMIM
Accession: SCV000839591.3
First in ClinVar: Oct 14, 2018 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Pathogenic
(Jun 24, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC |
OMIM
Accession: SCV001976535.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in … (more)
Colorectal Cancer In a relatively high frequency of colorectal cancers (114500), Samuels et al. (2004) identified a his1047-to-arg (H1047R) mutation in the PIK3CA gene; in vitro studies showed that the H1047R mutant has increased lipid kinase activity. Breast Cancer In 5 breast tumors (114480), 7 epithelial ovarian tumors (167000), and 1 colorectal tumor from a series of 284 primary human tumors, Campbell et al. (2004) identified the H1047R mutation, which is caused by a 3140A-G transition in exon 20. Lee et al. (2005) identified a somatic H1047R mutation in 21 breast cancer tumors, 4 gastric cancer (137215) tumors, 1 hepatocellular carcinoma (114550), and 1 nonsmall cell lung cancer (211980). CLOVE Syndrome In a 2-year-old boy and an unrelated 1-year-old girl with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome; 612918), Kurek et al. (2012) identified somatic mosaicism for the H1047R mutation in affected tissues from multiple embryonic lineages, with a mutant allele frequency ranging from 16 to 23%. Kurek et al. (2012) also stated that they had identified somatic mosaicism for H1047R in 3 patients who had been diagnosed with Klippel-Trenaunay-Weber syndrome (149000), an overgrowth syndrome with features overlapping those of CLOVE syndrome. Lindhurst et al. (2012) sequenced the PIK3CA gene in 10 individuals with an 'unclassified' syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified a somatic H1047R variant in 7 affected individuals, with mutation burdens ranging from less than 1% to 35% in affected tissues and fibroblast cultures. The features of the 'unclassified' syndrome were consistent with CLOVE syndrome. Seborrheic Keratosis Hafner et al. (2007) identified a heterozygous somatic H1047R mutation in a seborrheic keratosis lesion (182000). The authors emphasized that this is a benign lesion and noted that the same mutation had been observed in cancerous lesions. Macrodactyly Rios et al. (2013) identified the H1047R mutation in affected tissue from an individual (patient 6) with macrodactyly (155500). Immunochemistry showed increased staining in macrodactyly cells from patient 6 compared to control cells, indicating greater levels of ser473-phosphorylated AKT (164730) through increased activation of the PI3K-AKT cell signaling axis. Cerebral Cavernous Malformations 4 In samples of cerebral cavernous malformations-4 (CCM4; 619538) from 10 unrelated patients with sporadic occurrence of the disease, Peyre et al. (2021) identified a somatic H1047R mutation in the PIK3CA gene. The mutation was found by targeted DNA sequencing. PIK3CA-mutant CCMs showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with an activating mutation. Variant Function Using in situ genetic lineage tracing and limiting dilution transplantation, Koren et al. (2015) elucidated the potential of PIK3CA(H1047R) to induce multipotency during tumorigenesis in the mammary gland. The authors showed that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5 (606667)-positive and luminal keratin-8 (KRT8; 148060)-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multilineage mammary tumors. Moreover, Koren et al. (2015) showed that the tumor cell of origin influences the frequency of malignant mammary tumors. Koren et al. (2015) concluded that their results defined a key effect of PIK3CA(H1047R) on mammary cell fate in the preneoplastic mammary gland and showed that the cell of origin of PIK3CA(H1047R) tumors dictates their malignancy, thus revealing a mechanism underlying tumor heterogeneity and aggressiveness. Van Keymeulen et al. (2015) found that oncogenic PIK3CA(H1047R) mutant expression at physiologic levels in basal cells using keratin (K)5 (148040)-CreER(T2) mice induced the formation of luminal estrogen receptor (ER; 133430)-positive/progesterone receptor (PR; 607311)-positive tumors, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER+PR+ tumors or basal-like ER-PR- tumors. Concomitant deletion of p53 (191170) and expression of Pik3ca(H1047R) accelerated tumor development and induced more aggressive mammary tumors. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumors. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells. Van Keymeulen et al. (2015) concluded that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumor initiation, setting the stage for future intratumoral heterogeneity. (less)
|
|
|
Likely pathogenic
(Mar 19, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Rare venous malformation |
Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038944.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 3
|
|
|
Likely pathogenic
(Mar 19, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Rare combined vascular malformation |
Institute of Tissue Medicine and Pathology, University of Bern
Accession: SCV005038945.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 27, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
PIK3CA-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005351185.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
show
The PIK3CA c.3140A>G variant is predicted to result in the amino acid substitution p.His1047Arg. This variant has been reported to be mosaic in several individuals with CLOVES syndrome or megalencephaly-capillary malformation syndrome (Kurek et al. 2012. PubMed ID: 22658544; D'Gama et al. 2015. PubMed ID: 25599672; Mirzaa et al. 2016. PubMed ID: 27631024). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 01, 2015)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
PIK3CA Related Overgrowth Spectrum |
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV000255984.2
First in ClinVar: Oct 22, 2015 Last updated: Oct 07, 2023 |
Observation:
2
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Indication for testing: Lipoma
Tissue: FFPE
Platform type: Next-Generation Sequencing
Observation 2
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Indication for testing: Polydactyly; Syndactyly; Other specified congenital abnormalities
Tissue: FFPE
Platform Type: Next-Generation Sequencing
|
|
|
Pathogenic
(Dec 01, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ovarian neoplasm |
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923968.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Platform type: next-gen sequencing
|
|
|
Pathogenic
(Jun 02, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
CLOVES syndrome |
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002583480.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Jun 01, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
CLOVES syndrome |
Solve-RD Consortium
Accession: SCV005091336.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Observation: 1
Collection method: provider interpretation
Allele origin: inherited
Affected status: yes
Observation 1
Collection method: provider interpretation
Allele origin: inherited
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Breast carcinoma |
Medical Oncology, Institut Jules Bordet
Accession: SCV003803732.2
First in ClinVar: Feb 25, 2023 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Sex: female
|
|
|
Pathogenic
(Sep 30, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Cerebrofacial Vascular Metameric Syndrome (CVMS)
(Somatic mutation)
|
James Bennett Lab, Seattle Childrens Research Institute
Accession: SCV001960168.2
First in ClinVar: Oct 21, 2021 Last updated: Aug 03, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Comment on evidence:
"gain_of_function_variant" was previously submitted as the functional consequence for NM_006218.4:c.3140A>G, but without providing the result of a functional assay.
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
CLOVES syndrome |
GeneReviews
Accession: SCV000086944.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
Observation: 1
Collection method: literature only
Allele origin: unknown
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: unknown
Affected status: not provided
|
|
Comment:
Comment:
PS3, PM1, PM2, PM5, PP2, PP3, PP4, PP5
Comment:
PS4, PS3, PM2
Comment:
This variant substitutes the histidine with arginine at position 1047 within the PIK3CA kinase domain. This is a recurrent pathogenic variant. Several unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the somatic activating PIK3CA p.His1047Arg variant have previously been reported (PMID: 25681199, PMID: 26637981, PMID: 24903541, PMID: 30180809, PMID: 28328134 and others).
Comment:
Reported as a somatic variant in various tumor samples (Campbell et al., 2004; Li et al., 2005); Published functional studies demonstrate increased lipid kinase activity and transforming activities, and a mouse model with this variant demonstrated increased body weight, increased organ size, and severe metabolic defects (Ikenoue et al., 2005; Kinross et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16322209, 15289301, 15016963, 25599672, 23100325, 25550458, 15930273, 16432179, 19805105, 21708979, 15520168, 15784156, 27631024, 24903541, 22658544, 32770747, 34568242, 34075207)
Comment:
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Comment:
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.46 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.66 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013652 /PMID: 25599672). Different missense changes at the same codon (p.His1047Gln, p.His1047Leu, p.His1047Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013653, VCV000039705, VCV000376481 /PMID: 22729224, 28151489 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in glioma, based on the following evidence: 1) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B). 2) Diagnostic significance based on multiple small studies (Evidence Level C; PMID: 31250151).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 24705252, 31348837, 25230881).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22142829, 24436047, 34166060, 34401606).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 35023985, 31036078, 34185076).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in colorectal cancer, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 15930273). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 15016963, 22810696).
Comment:
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in diffuse glioma, H3 G34 mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17376864, 26627007). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 24705251, 35195909, 35303099).
Comment:
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in neuroblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17376864, 26627007). 3) Assists in diagnosis alone or along with other biomarkers based on small studies or few case reports (Evidence Level D; PMIDs: 16822308, 21225506, 25811750).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in adenoid cystic carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 23685749, 23778141, 33290961, 31483290, 29682203).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in rosette-forming glioneuronal tumor of fourth ventricule, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 31250151, 32859279, 35293634, 21997360, 23547894, 24806303, 27893178, 28912153).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in macrocystic lymphatic malformation, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 16432179, 19805105, 26627007). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 25681199, 29217067, 31536475).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in nasopharyngeal carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 16432179, 19805105, 26627007). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24672248, 28581676, 34194007, 37371623).
Comment:
PIK3CA: PS2:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP2
Comment:
The PIK3CA c.3140A>G (p.His1047Arg) variant was identified. This variant has been reported in numerous individuals affected with PROS disorders (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; Mirzaa G et al., PMID: 27631024; Kurek KC et al, PMID: 22658544). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic both in a germline and a somatic state by numerous submitters, including an expert panel (ClinVar ID: 13652). It has also been reported in multiple cases in the cancer database COSMIC (COSMIC ID: COSV55873195). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The PIK3CA c.3140A>G (p.His1047Arg) variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain (Zhao L et al., PMID: 18268322; Samuels Y et al., PMID: 15016963; Lai A et al., PMID: 35997716). Functional studies showed autonomous activation and enhanced Akt-mTOR signaling in vitro and tumorigenesis in vivo, indicating that this variant impacts protein function (Yuan W et al., PMID: 22370636; Loconte DC et al., PMID: 25915946; Rios JJ et al., PMID: 23100325; Lindhurst MJ et al., PMID: 22729222; Tikoo A et al., PMID: 22666336). Other variants in the same codon, c.3140A>T (p.His1047Leu) and c.3139C>T (p.His1047Tyr), have been reported in individuals with PROS disorders and are considered pathogenic (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; ClinVar ID: 13653, 39705). The PIK3CA gene is defined by the ClinGen Brain Malformation Expert Panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (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.3140A>G (p.His1047Arg) variant is classified as pathogenic.
Comment:
The PIK3CA c.3140A>G variant is predicted to result in the amino acid substitution p.His1047Arg. This variant has been reported to be mosaic in several individuals with CLOVES syndrome or megalencephaly-capillary malformation syndrome (Kurek et al. 2012. PubMed ID: 22658544; D'Gama et al. 2015. PubMed ID: 25599672; Mirzaa et al. 2016. PubMed ID: 27631024). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses. | Laurie S | Nature medicine | 2025 | PMID: 39825153 |
| PIK3CA-Related Overgrowth Spectrum. | Adam MP | - | 2023 | PMID: 23946963 |
| Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations. | Peyre M | The New England journal of medicine | 2021 | PMID: 34496175 |
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations. | Zenner K | JCI insight | 2019 | PMID: 31536475 |
| Molecular heterogeneity of the cerebriform connective tissue nevus in mosaic overgrowth syndromes. | Keppler-Noreuil KM | Cold Spring Harbor molecular case studies | 2019 | PMID: 31371346 |
| PIK3CA c.3140A>G mutation in a patient with suspected Proteus Syndrome: a case report. | Valentini V | Clinical case reports | 2018 | PMID: 29988677 |
| A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. | Mayer IA | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 27126994 |
| Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. | Dogruluk T | Cancer research | 2015 | PMID: 26627007 |
| Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. | Van Keymeulen A | Nature | 2015 | PMID: 26266985 |
| PIK3CA(H1047R) induces multipotency and multi-lineage mammary tumours. | Koren S | Nature | 2015 | PMID: 26266975 |
| Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. | D'Gama AM | Annals of neurology | 2015 | PMID: 25599672 |
| Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. | Rios JJ | Human molecular genetics | 2013 | PMID: 23100325 |
| 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 |
| Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. | Yuan W | Oncogene | 2013 | PMID: 22370636 |
| 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 |
| Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. | Lindhurst MJ | Nature genetics | 2012 | PMID: 22729222 |
| Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. | Kurek KC | American journal of human genetics | 2012 | PMID: 22658544 |
| Structural effects of oncogenic PI3Kα mutations. | Gabelli SB | Current topics in microbiology and immunology | 2010 | PMID: 20593314 |
| 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 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 |
| High frequency of mutations of the PIK3CA gene in human cancers. | Samuels Y | Science (New York, N.Y.) | 2004 | PMID: 15016963 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f4d8f50e-a120-47e5-8b69-0a8921149fde | - | - | - | - |
| click to load more citations click to collapse | ||||
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Dec 29, 2025 | RCV000438435.13 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Oct 7, 2024 | RCV000487449.13 | ||
|
Tier II (Potential)
- diagnostic
- supports diagnosis
(1)
|
Feb 28, 2024 | RCV006253564.1 | ||
|
Tier II (Potential)
- diagnostic
- supports diagnosis
(1)
|
Mar 8, 2024 | RCV006253555.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
May 10, 2023 | RCV006253561.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Mar 3, 2025 | RCV006253563.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Mar 20, 2023 | RCV006253557.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Oct 17, 2023 | RCV006253558.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Apr 17, 2024 | RCV006253559.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Dec 2, 2022 | RCV006253560.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
May 8, 2025 | RCV006253556.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Nov 9, 2022 | RCV006253562.1 | ||
| click to load more conditions click to collapse | ||||
Submissions - Somatic
|
Clinical impact
Help
The submitted somatic clinical impact for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Mar 20, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Glioma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104431.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in glioma, based on the following evidence: 1) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B). 2) Diagnostic significance based on multiple small studies (Evidence Level C; PMID: 31250151). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Nov 09, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Diffuse midline glioma, H3 K27M-mutant |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104433.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 24705252, 31348837, 25230881). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Dec 02, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Embryonal rhabdomyosarcoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104434.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22142829, 24436047, 34166060, 34401606). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (May 10, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104444.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 35023985, 31036078, 34185076). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Oct 17, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Colorectal cancer |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104452.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in colorectal cancer, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 15930273). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 15016963, 22810696). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Apr 17, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adenoid cystic carcinoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104470.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in adenoid cystic carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 23685749, 23778141, 33290961, 31483290, 29682203). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Oct 07, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Rosette-forming glioneuronal tumor |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104495.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in rosette-forming glioneuronal tumor of fourth ventricule, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 31250151, 32859279, 35293634, 21997360, 23547894, 24806303, 27893178, 28912153). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Mar 03, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cavernous lymphangioma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104500.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in macrocystic lymphatic malformation, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 16432179, 19805105, 26627007). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 25681199, 29217067, 31536475). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (May 08, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Nasopharyngeal carcinoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104510.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in nasopharyngeal carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 16432179, 19805105, 26627007). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24672248, 28581676, 34194007, 37371623). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier II (Potential)
- Diagnostic
-
supports diagnosis (Feb 28, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Diffuse glioma, H3 G34 mutant |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104462.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in diffuse glioma, H3 G34 mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17376864, 26627007). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 24705251, 35195909, 35303099). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier II (Potential)
- Diagnostic
-
supports diagnosis (Mar 08, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Neuroblastoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104464.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in neuroblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17376864, 26627007). 3) Assists in diagnosis alone or along with other biomarkers based on small studies or few case reports (Evidence Level D; PMIDs: 16822308, 21225506, 25811750). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Dec 29, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neoplasm |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094537.3
First In ClinVar: Aug 11, 2024 Last updated: Jan 03, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
Comment:
The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25424831). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021)
Comment:
PS3, PM1, PM2, PM5, PP2, PP3, PP4, PP5
Comment:
PS4, PS3, PM2
Comment:
This variant substitutes the histidine with arginine at position 1047 within the PIK3CA kinase domain. This is a recurrent pathogenic variant. Several unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the somatic activating PIK3CA p.His1047Arg variant have previously been reported (PMID: 25681199, PMID: 26637981, PMID: 24903541, PMID: 30180809, PMID: 28328134 and others).
Comment:
Reported as a somatic variant in various tumor samples (Campbell et al., 2004; Li et al., 2005); Published functional studies demonstrate increased lipid kinase activity and transforming activities, and a mouse model with this variant demonstrated increased body weight, increased organ size, and severe metabolic defects (Ikenoue et al., 2005; Kinross et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16322209, 15289301, 15016963, 25599672, 23100325, 25550458, 15930273, 16432179, 19805105, 21708979, 15520168, 15784156, 27631024, 24903541, 22658544, 32770747, 34568242, 34075207)
Comment:
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Comment:
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.46 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.66 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013652 /PMID: 25599672). Different missense changes at the same codon (p.His1047Gln, p.His1047Leu, p.His1047Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013653, VCV000039705, VCV000376481 /PMID: 22729224, 28151489 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in glioma, based on the following evidence: 1) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B). 2) Diagnostic significance based on multiple small studies (Evidence Level C; PMID: 31250151).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 24705252, 31348837, 25230881).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22142829, 24436047, 34166060, 34401606).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, based on the following evidence: 1) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 35023985, 31036078, 34185076).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in colorectal cancer, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 15930273). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 15016963, 22810696).
Comment:
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in diffuse glioma, H3 G34 mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17376864, 26627007). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 24705251, 35195909, 35303099).
Comment:
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in neuroblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 17376864, 26627007). 3) Assists in diagnosis alone or along with other biomarkers based on small studies or few case reports (Evidence Level D; PMIDs: 16822308, 21225506, 25811750).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in adenoid cystic carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 23685749, 23778141, 33290961, 31483290, 29682203).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in rosette-forming glioneuronal tumor of fourth ventricule, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 19805105, 22120714, 22729222). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 31250151, 32859279, 35293634, 21997360, 23547894, 24806303, 27893178, 28912153).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in macrocystic lymphatic malformation, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 16432179, 19805105, 26627007). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 25681199, 29217067, 31536475).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in nasopharyngeal carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 16432179, 19805105, 26627007). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24672248, 28581676, 34194007, 37371623).
Comment:
PIK3CA: PS2:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP2
Comment:
The PIK3CA c.3140A>G (p.His1047Arg) variant was identified. This variant has been reported in numerous individuals affected with PROS disorders (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; Mirzaa G et al., PMID: 27631024; Kurek KC et al, PMID: 22658544). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic both in a germline and a somatic state by numerous submitters, including an expert panel (ClinVar ID: 13652). It has also been reported in multiple cases in the cancer database COSMIC (COSMIC ID: COSV55873195). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The PIK3CA c.3140A>G (p.His1047Arg) variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain (Zhao L et al., PMID: 18268322; Samuels Y et al., PMID: 15016963; Lai A et al., PMID: 35997716). Functional studies showed autonomous activation and enhanced Akt-mTOR signaling in vitro and tumorigenesis in vivo, indicating that this variant impacts protein function (Yuan W et al., PMID: 22370636; Loconte DC et al., PMID: 25915946; Rios JJ et al., PMID: 23100325; Lindhurst MJ et al., PMID: 22729222; Tikoo A et al., PMID: 22666336). Other variants in the same codon, c.3140A>T (p.His1047Leu) and c.3139C>T (p.His1047Tyr), have been reported in individuals with PROS disorders and are considered pathogenic (McNulty SN et al., PMID: 31585106; Keppler-Noreuil KM et al., PMID: 24782230; ClinVar ID: 13653, 39705). The PIK3CA gene is defined by the ClinGen Brain Malformation Expert Panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (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.3140A>G (p.His1047Arg) variant is classified as pathogenic.
Comment:
The PIK3CA c.3140A>G variant is predicted to result in the amino acid substitution p.His1047Arg. This variant has been reported to be mosaic in several individuals with CLOVES syndrome or megalencephaly-capillary malformation syndrome (Kurek et al. 2012. PubMed ID: 22658544; D'Gama et al. 2015. PubMed ID: 25599672; Mirzaa et al. 2016. PubMed ID: 27631024). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Feature Reviews of the Molecular Mechanisms of Nasopharyngeal Carcinoma. | Liao LJ | Biomedicines | 2023 | PMID: 37371623 |
| Beyond Midline: Diffuse Hemispheric Glioma, H3 K27M-Mutant with Aggressive Behavior. | Valério E | Journal of neuropathology and experimental neurology | 2022 | PMID: 35303099 |
| Rosette-forming glioneuronal tumours are midline, FGFR1-mutated tumours. | Appay R | Neuropathology and applied neurobiology | 2022 | PMID: 35293634 |
| The prognostic significance of further genotyping H3G34 diffuse hemispheric gliomas. | Vuong HG | Cancer | 2022 | PMID: 35195909 |
| PIK3CA Mutations in Diffuse Gliomas: An Update on Molecular Stratification, Prognosis, Recurrence, and Aggressiveness. | Brito C | Clinical Medicine Insights. Oncology | 2022 | PMID: 35023985 |
| Germline ATM mutation and somatic PIK3CA and BCOR mutations found in an infant with aggressive orbital embryonal rhabdomyosarcoma. | Jaru-Ampornpan P | American journal of ophthalmology case reports | 2021 | PMID: 34401606 |
| Nasopharyngeal carcinoma: an evolving paradigm. | Wong KCW | Nature reviews. Clinical oncology | 2021 | PMID: 34194007 |
| The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. | Louis DN | Neuro-oncology | 2021 | PMID: 34185076 |
| Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium. | Shern JF | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2021 | PMID: 34166060 |
| The utility of TP53 and PIK3CA mutations as prognostic biomarkers in salivary adenoid cystic carcinoma. | Adderley H | Oral oncology | 2021 | PMID: 33290961 |
| Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor. | Lucas CG | Acta neuropathologica communications | 2020 | PMID: 32859279 |
| Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant. | Dufour C | Brain pathology (Zurich, Switzerland) | 2020 | PMID: 31348837 |
| Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations. | Zenner K | JCI insight | 2019 | PMID: 31536475 |
| Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. | Ho AS | The Journal of clinical investigation | 2019 | PMID: 31483290 |
| Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. | Sievers P | Acta neuropathologica | 2019 | PMID: 31250151 |
| PIK3CA activating mutations are associated with more disseminated disease at presentation and earlier recurrence in glioblastoma. | Tanaka S | Acta neuropathologica communications | 2019 | PMID: 31036078 |
| Mutation analysis of the EGFR pathway genes, EGFR, RAS, PIK3CA, BRAF, and AKT1, in salivary gland adenoid cystic carcinoma. | Saida K | Oncotarget | 2018 | PMID: 29682203 |
| Systematic Functional Annotation of Somatic Mutations in Cancer. | Ng PK | Cancer cell | 2018 | PMID: 29533785 |
| Etiology and Genetics of Congenital Vascular Lesions. | Queisser A | Otolaryngologic clinics of North America | 2018 | PMID: 29217067 |
| Comprehensive genetic characterization of rosette-forming glioneuronal tumors: independent component analysis by tissue microdissection. | Kitamura Y | Brain pathology (Zurich, Switzerland) | 2018 | PMID: 27893178 |
| Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. | Mackay A | Cancer cell | 2017 | PMID: 28966033 |
| Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures. | Johnson A | The oncologist | 2017 | PMID: 28912153 |
| Comprehensive genomic profiling of different subtypes of nasopharyngeal carcinoma reveals similarities and differences to guide targeted therapy. | Ali SM | Cancer | 2017 | PMID: 28581676 |
| Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. | Dogruluk T | Cancer research | 2015 | PMID: 26627007 |
| Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. | Dogruluk T | Cancer research | 2015 | PMID: 26627007 |
| PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. | King D | Journal of pediatric hematology/oncology | 2015 | PMID: 25811750 |
| Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. | Luks VL | The Journal of pediatrics | 2015 | PMID: 25681199 |
| Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. | Jones C | Nature reviews. Cancer | 2014 | PMID: 25230881 |
| FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle. | Gessi M | Journal of neuropathology and experimental neurology | 2014 | PMID: 24806303 |
| Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. | Taylor KR | Nature genetics | 2014 | PMID: 24705252 |
| The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. | Wu G | Nature genetics | 2014 | PMID: 24705251 |
| Oncogene mutational profile in nasopharyngeal carcinoma. | Zhang ZC | OncoTargets and therapy | 2014 | PMID: 24672248 |
| Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. | Shern JF | Cancer discovery | 2014 | PMID: 24436047 |
| Whole exome sequencing of adenoid cystic carcinoma. | Stephens PJ | The Journal of clinical investigation | 2013 | PMID: 23778141 |
| The mutational landscape of adenoid cystic carcinoma. | Ho AS | Nature genetics | 2013 | PMID: 23685749 |
| Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer. | Thommen F | Clinical neuropathology | 2013 | PMID: 23547894 |
| Comprehensive molecular characterization of human colon and rectal cancer. | Cancer Genome Atlas Network | Nature | 2012 | PMID: 22810696 |
| Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. | Lindhurst MJ | Nature genetics | 2012 | PMID: 22729222 |
| Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. | Shukla N | Clinical cancer research : an official journal of the American Association for Cancer Research | 2012 | PMID: 22142829 |
| Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases. | Hon WC | Oncogene | 2012 | PMID: 22120714 |
| Recurrent PIK3CA mutations in rosette-forming glioneuronal tumor. | Ellezam B | Acta neuropathologica | 2012 | PMID: 21997360 |
| EGFR, PIK3CA and PTEN gene status and their protein product expression in neuroblastic tumours. | Izycka-Swieszewska E | Folia neuropathologica | 2010 | PMID: 21225506 |
| A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. | Mandelker D | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19805105 |
| Rare cancer-specific mutations in PIK3CA show gain of function. | Gymnopoulos M | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17376864 |
| Mutations in PIK3CA are infrequent in neuroblastoma. | Dam V | BMC cancer | 2006 | PMID: 16822308 |
| Cancer-specific mutations in PIK3CA are oncogenic in vivo. | Bader AG | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 16432179 |
| Functional analysis of PIK3CA gene mutations in human colorectal cancer. | Ikenoue T | Cancer research | 2005 | PMID: 15930273 |
| High frequency of mutations of the PIK3CA gene in human cancers. | Samuels Y | Science (New York, N.Y.) | 2004 | PMID: 15016963 |
| click to load more citations click to collapse | ||||
Text-mined citations for rs121913279 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 11, 2026
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.