rs121913273
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP2PM2_SupportingPS4PS2_Moderate
This summary comes from the ClinGen Evidence Repository: The c.1624G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu542Lys). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID:22658544). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 25722288, 25681199, 22658544, 29446767, 26851524, 25292196, 23100325; identified in 1 individual with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation, at least 6 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), at least 9 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, and at least 9 tumor samples in the literature and COSMIC). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PS2_M, PS4_VS, PM2_P, PP2; 12 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA333572/MONDO:0016054/018
Frequency
Genomes: not found (cov: 32)
Consequence
PIK3CA
NM_006218.4 missense
NM_006218.4 missense
Scores
10
3
6
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 8 ACMG points.
PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PIK3CA | NM_006218.4 | c.1624G>A | p.Glu542Lys | missense_variant | 10/21 | ENST00000263967.4 | NP_006209.2 | |
| PIK3CA | XM_006713658.5 | c.1624G>A | p.Glu542Lys | missense_variant | 10/21 | XP_006713721.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PIK3CA | ENST00000263967.4 | c.1624G>A | p.Glu542Lys | missense_variant | 10/21 | 2 | NM_006218.4 | ENSP00000263967 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:39Other:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Oct 01, 2020 | This variant has previously been reported in several unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 31536475, PMID: 25681199, PMID: 29985963 and others). The p.E542K variant substitutes the glutamic acid at position 542 with lysine within the PIK helical domain of the PIK3CA protein (UniProt P42336). This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 26627007). - |
| Pathogenic, no assertion criteria provided | case-control | Department of Medical Genetics, University of Szeged | Sep 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Classified as pathogenic by the ClinGen Brain Malformations Variant Curation Expert Panel (SCV001949964.2); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25599672, 25044986, 29446767, 27631024, 26851524, 23100325, 23066039, 22658544, 22357840, 24374682, 33502802, 34606700) - |
Ovarian neoplasm Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 12, 2011 | - - |
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
CLOVES syndrome Pathogenic:3
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2012 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Institute of Tissue Medicine and Pathology, University of Bern | Mar 19, 2024 | - - |
| Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 15, 2013 | - - |
Non-small cell lung carcinoma Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 12, 2011 | - - |
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Glioblastoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Prostate adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Carcinoma of esophagus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell lung carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
HEMIFACIAL MYOHYPERPLASIA, SOMATIC Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2012 | - - |
Rare venous malformation Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Institute of Tissue Medicine and Pathology, University of Bern | Mar 19, 2024 | - - |
Cerebrofacial Vascular Metameric Syndrome (CVMS) Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | James Bennett Lab, Seattle Childrens Research Institute | Sep 30, 2021 | - - |
Cowden syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 27, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 542 of the PIK3CA protein (p.Glu542Lys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 31944). This missense change has been observed in individual(s) with PIK3CA-related disorders (PMID: 25599672, 26851524, 27631024). In at least one individual the variant was observed to be de novo. - |
Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Personalized Medicine Clinic, Tartu University Hospital | - | - - |
Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen Brain Malformations Variant Curation Expert Panel | Feb 12, 2022 | The c.1624G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu542Lys). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 22658544). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 25722288, 25681199, 22658544, 29446767, 26851524, 25292196, 23100325; identified in 1 individual with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation, at least 6 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), at least 9 individuals with segmental overgrowth or vascular malformation of a limb or region of the body, and at least 9 tumor samples in the literature and COSMIC). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PS2_M, PS4_VS, PM2_P, PP2; 12 points (VCEP specifications version 1; Approved: 1/31/2021) - |
Neoplasm of brain Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hepatocellular carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Small cell lung carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
PIK3CA-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 24, 2024 | The PIK3CA c.1624G>A variant is predicted to result in the amino acid substitution p.Glu542Lys. This is a recurrent somatic variant reported in individuals with dysplastic megalencephaly, hemimegalencephaly, or CLOVES syndrome (Kurek et al. 2012. PubMed ID: 22658544; Mirzaa et al. 2013. PubMed ID: 23946963; D’Gama et al. 2015. PubMed ID: 25599672; Mirzaa et al. 2016. PubMed ID: 27631024). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/31944/). This variant is interpreted as pathogenic. - |
Papillary renal cell carcinoma, sporadic Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2012 | - - |
CLAPO syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2012 | - - |
Lip and oral cavity carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Apr 30, 2019 | - - |
PIK3CA related overgrowth syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Nov 03, 2023 | A PIK3CA c.1624G>A (p.Glu542Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Rodriguez-Laguna L et al., PMID: 29446767; Mirzaa G et al., PMID: 27631024; Osborn AJ et al., PMID: 25292196; Kurek KC et al., PMID: 22658544; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199). The PIK3CA c.1624G>A (p.Glu542Lys) variant has been classified as a pathogenic variant both in a germline and a somatic state by numerous laboratories as well as by an expert panel as a germline pathogenic variant (ClinVar Variation ID: 31944). This variant resides within the helical domain of the p110⍺ catalytic subunit, amino acids 517-694, of PIK3CA that is defined as a critical functional domain and constitutes a mutational hotspot (Madsen R et al., PMID: 30197175; Gymnopoulos M et al., PMID: 17376864). The PIK3CA c.1624G>A (p.Glu542Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies show that this lysine substitution at codon 542 leads to increased lipid kinase activity of p110a, autonomous phosphorylation of AKT, and oncogenic cellular transformation, indicating that this variant impacts protein function (Gymnopoulos M et al., PMID: 17376864; Ikenoue T et al., PMID: 15930273; Kang S et al., PMID: 15647370). The PIK3CA gene is defined by the ClinGen Brain Malformations Variant Curation Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID: 35997716). A large number of PI3K/AKT pathway inhibitors are currently under clinical study, in both PROS disorders and cancer (Jin N et al., PMID: 34779417; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.1624G>A (p.Glu542Lys) variant is classified as pathogenic. - |
Malignant neoplasm of body of uterus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lung adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Abnormal cardiovascular system morphology Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | MAGI's Lab - Research, MAGI Group | - | - - |
Transitional cell carcinoma of the bladder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of uterine cervix Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm Other:1
| -, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
PIK3CA-related overgrowth Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Pathogenic and reported on 06-14-2017 by Clinical Genomics Lab at Washington University in St. Louis. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Benign
T;.
Polyphen
D;.
Vest4
MutPred
Gain of methylation at E542 (P = 0.0074);Gain of methylation at E542 (P = 0.0074);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at