ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)

dbSNP: rs1057519925
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Undiagnosed Diseases Network, NIH RCV000991209 SCV001142587 pathogenic Megalencephaly-capillary malformation-polymicrogyria syndrome 2019-05-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV000991209 SCV001521015 pathogenic Megalencephaly-capillary malformation-polymicrogyria syndrome 2020-06-25 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526693 SCV001737114 pathogenic CLOVES syndrome criteria provided, single submitter clinical testing
GeneDx RCV001775789 SCV002013346 pathogenic not provided 2022-10-14 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: increased phosphorylation of AKT on serine 473 (Rudd et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23352210, 29759595, 26619011, 21531001, 27834349, 27631024, 30063105, 27037860, 31263565, 21266528)
Invitae RCV001861479 SCV002247469 pathogenic Cowden syndrome 2021-06-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 453 of the PIK3CA protein (p.Glu453Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with PIK3CA-associated overgrowth conditions (PMID: 27631024, 27631024, 28151489, ClinVar). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376470). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Daryl Scott Lab, Baylor College of Medicine RCV002244865 SCV002515365 pathogenic PIK3CA-related disorder 2022-02-01 criteria provided, single submitter clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV001775789 SCV002525708 pathogenic not provided 2021-08-26 criteria provided, single submitter clinical testing This variant has previously been reported in multiple unrelated individuals with a molecular diagnosis of PROS, including those with reported overgrowth and macrodactyly (PMID: 27631024, PMID: 31263565). The p.Glu453Lys variant substitutes the glutamic acid at position 453 with lysine within the C2 phosphatidylinositol 3-kinase domain of the PIK3CA protein (UniProt P42336, aa# 330-487). This is a recurrent hotspot. PIK3CA variants associated with PROS overlap those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002472374 SCV002557944 pathogenic PIK3CA related overgrowth syndrome 2022-09-02 criteria provided, single submitter clinical testing A suspected mosaic missense variant was identified, NM_006218.2(PIK3CA):c.1357G>A in exon 8 of the PIK3CA gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to a lysine at position 453 of the protein; NP_006209.2(PIK3CA):p.(Glu453Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located within the C2 domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in patients with overgrowth disorders (Mirzaa, G. et al . (2016); Piacitelli, A. et al . (2018)). A different variant in the same codon resulting in an inframe deletion has also been shown to cause the same condition (Mirzaa, G. et al . (2016); Riviere, J-B. et al . (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg RCV001526693 SCV003928007 pathogenic CLOVES syndrome 2023-06-01 criteria provided, single submitter clinical testing This variant has been identified by standard clinical testing. somatic mutation
Database of Curated Mutations (DoCM) RCV000430361 SCV000506827 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440626 SCV000506828 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422944 SCV000506829 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433137 SCV000506830 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443243 SCV000506831 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423945 SCV000506832 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434215 SCV000506833 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442682 SCV000506834 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425038 SCV000506835 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435327 SCV000506836 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785580 SCV000924154 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
MAGI's Lab - Research, MAGI Group RCV001327961 SCV001437637 pathogenic Abnormal cardiovascular system morphology no assertion criteria provided provider interpretation

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