Total submissions: 37
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001836714 | SCV001949964 | pathogenic | Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes | 2022-02-12 | reviewed by expert panel | curation | 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) |
Gene |
RCV000416776 | SCV001830827 | pathogenic | not provided | 2023-02-27 | criteria provided, single submitter | clinical testing | 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) |
Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV000416776 | SCV002525701 | pathogenic | not provided | 2020-10-01 | criteria provided, single submitter | clinical testing | 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). |
Invitae | RCV002513230 | SCV003525379 | pathogenic | Cowden syndrome | 2022-10-27 | criteria provided, single submitter | clinical testing | 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. |
Clinical Genomics Laboratory, |
RCV003458190 | SCV004176951 | pathogenic | PIK3CA related overgrowth syndrome | 2023-11-03 | criteria provided, single submitter | clinical testing | 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. |
Prevention |
RCV003894820 | SCV004717831 | pathogenic | PIK3CA-related condition | 2024-01-03 | criteria provided, single submitter | clinical testing | 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 (http://gnomad.broadinstitute.org), 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. |
OMIM | RCV000024622 | SCV000050488 | pathogenic | CLOVES syndrome | 2012-06-08 | no assertion criteria provided | literature only | |
Gene |
RCV000024622 | SCV000086942 | pathologic | CLOVES syndrome | 2013-08-15 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
Laboratory for Molecular Medicine, |
RCV000151649 | SCV000199901 | pathogenic | Neoplasm of ovary | 2011-10-12 | no assertion criteria provided | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000154513 | SCV000204184 | pathogenic | Non-small cell lung carcinoma | 2011-10-12 | no assertion criteria provided | clinical testing | |
Department of Medical Genetics, |
RCV000416776 | SCV000258982 | pathogenic | not provided | 2015-09-01 | no assertion criteria provided | case-control | |
Database of Curated Mutations |
RCV000154513 | SCV000503916 | pathogenic | Non-small cell lung carcinoma | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421639 | SCV000503917 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431872 | SCV000503918 | pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442348 | SCV000503919 | pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000151649 | SCV000503920 | pathogenic | Neoplasm of ovary | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433007 | SCV000503921 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445059 | SCV000503922 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425548 | SCV000503923 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435811 | SCV000503924 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419905 | SCV000503925 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426691 | SCV000503926 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436932 | SCV000503927 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419440 | SCV000503928 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431000 | SCV000503929 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441707 | SCV000503930 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420078 | SCV000503931 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430763 | SCV000503932 | likely pathogenic | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438815 | SCV000503933 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
OMIM | RCV000709693 | SCV000839593 | pathogenic | CLAPO syndrome | 2012-06-08 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000151649 | SCV000923935 | pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research | |
Institute of Medical Sciences, |
RCV001255687 | SCV001432252 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research | |
MAGI's Lab - |
RCV001327962 | SCV001437638 | pathogenic | Abnormal cardiovascular system morphology | no assertion criteria provided | provider interpretation | ||
James Bennett Lab, |
RCV001730477 | SCV001960169 | pathogenic | Cerebrofacial Vascular Metameric Syndrome (CVMS) | 2021-09-30 | no assertion criteria provided | clinical testing | |
OMIM | RCV001728093 | SCV001976537 | pathogenic | CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC | 2012-06-08 | no assertion criteria provided | literature only | |
OMIM | RCV003764635 | SCV004697482 | pathogenic | HEMIFACIAL MYOHYPERPLASIA, SOMATIC | 2012-06-08 | no assertion criteria provided | literature only | |
Genome |
RCV003987334 | SCV004804559 | not provided | PIK3CA-related overgrowth | no assertion provided | phenotyping only | 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/. |