ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)

dbSNP: rs121913273
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Total submissions: 32
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Brain Malformations Variant Curation Expert Panel 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)
GeneDx RCV000416776 SCV001830827 pathogenic not provided 2021-01-22 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); 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, 24374682, 23100325, 25044986, 22357840, 22658544, 23066039, 26851524, 27631024, 29446767)
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital 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).
OMIM RCV000024622 SCV000050488 pathogenic CLOVES syndrome 2012-06-08 no assertion criteria provided literature only
GeneReviews RCV000024622 SCV000086942 pathologic CLOVES syndrome 2013-08-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000151649 SCV000199901 pathogenic Neoplasm of ovary 2011-10-12 no assertion criteria provided clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000154513 SCV000204184 pathogenic Non-small cell lung carcinoma 2011-10-12 no assertion criteria provided clinical testing
Department of Medical Genetics,University of Szeged RCV000416776 SCV000258982 pathogenic not provided 2015-09-01 no assertion criteria provided case-control
Database of Curated Mutations (DoCM) RCV000154513 SCV000503916 pathogenic Non-small cell lung carcinoma 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421639 SCV000503917 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431872 SCV000503918 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442348 SCV000503919 pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000151649 SCV000503920 pathogenic Neoplasm of ovary 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433007 SCV000503921 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445059 SCV000503922 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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 (DoCM) RCV000435811 SCV000503924 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419905 SCV000503925 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426691 SCV000503926 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436932 SCV000503927 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419440 SCV000503928 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431000 SCV000503929 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441707 SCV000503930 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420078 SCV000503931 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430763 SCV000503932 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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, University Hospital Cologne RCV000151649 SCV000923935 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Institute of Medical Sciences, Banaras Hindu University RCV001255687 SCV001432252 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research
MAGI's Lab - Research,MAGI Group RCV001327962 SCV001437638 pathogenic Abnormality of cardiovascular system morphology no assertion criteria provided provider interpretation
James Bennett Lab,Seattle Childrens Research Institute 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

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