ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.1633G>A (p.Glu545Lys)

dbSNP: rs104886003
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Total submissions: 48
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001092440 SCV001248954 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001262721 SCV001440692 likely pathogenic CLOVES syndrome 2019-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290591 SCV001478679 pathogenic PIK3CA related overgrowth spectrum 2021-01-08 criteria provided, single submitter clinical testing Variant summary: PIK3CA c.1633G>A (p.Glu545Lys) results in a conservative amino acid change located in the Phosphoinositide 3-kinase, accessory (PIK) domain (IPR001263) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247990 control chromosomes (gnomAD). c.1633G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth spectrum disorders (example: Baptiste-Riviere_2013, DGama_2016, Kuentz_2017, Mirzaa_2016, Yates_2018). In several of these patients, the variant was described as a mosaic mutation. In addition, somatic occurrence of this variant was also reported in a number tumors including but not limited to Breast Cancer and Seborrheic Keratosis (example: Hafner_2010, Juric_2019). These data indicate that the variant is very likely to be associated with disease. Several reports suggest that this variant is a hot-spot mutation. Consistent with these reports in functional studies, the variant was found to have greater lipid kinase activities. In vitro cell line studies expressing the variant also demonstrate constitutive activation of downstream components of PI3K signaling pathway. In transformation assays using NIH 3T3 cells, the variant induced more foci than the wild-type (Ikenoue_2005). Several ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic in the context of germline and somatic origin. Based on the evidence outlined above, the variant was classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001262721 SCV001737090 pathogenic CLOVES syndrome criteria provided, single submitter clinical testing
GeneDx RCV001092440 SCV001772130 pathogenic not provided 2021-04-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32901329, 30547809, 30341384, 28425981, 27631024, 26637981, 15950905, 16432179, 15930273, 24080956, 17376864, 23946963, 22729223, 22729224, 25599672, 29152088, 27317099)
Institute of Medical and Molecular Genetics,Hospital Universitario La Paz RCV001705591 SCV001934208 pathogenic Segmental undergrowth associated with lymphatic malformation 2021-04-06 criteria provided, single submitter clinical testing
Genomics For Life RCV001786329 SCV002028353 pathogenic Eccrine Angiomatous Hamartoma 2021-10-21 criteria provided, single submitter clinical testing A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are associated with PIK3CA-Related Overgrowth Spectrum (PROS) and the PIK3CA c.1633G>A; p.(Glu545Lys) (Chr3:g.178936091G>A) variant has previously been reported in patients with PROS, CLOVES syndrome, fibroadipose hyperplasia and isolated macrodactyly (PMID: 28151489, 29661094) The PIK3CA c.1633G>A; p.(Glu545Lys) variant results in a p110 alpha-helical domain substitution (PMID:26637981), activates AKT, disrupts normal EC-characteristic monolayer morphology as visualized by phase-contrast microscopy, results in loss of ECM fibronectin, and strongly downregulates ANGPT2 and PDGF-B mRNA expression as measured by real-time quantitative PCR. Plasminogen system-components are also somewhat dysregulated by the variant PIK3CA c.1633G>A; p.(Glu545Lys) (PMID:26637981). The variant is located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation: using strength Strong because Hot-spot of length 17 amino-acids has 21 non-VUS missense/in-frame variants (21 pathogenic and 0 benign), pathogenicity = 100.0%, qualifies as a dense hot-spot. The variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium: GnomAD exomes allele count = 1 is less than 5 for gene PIK3CA (good gnomAD exomes coverage = 42.7) and the variant is not found in gnomAD genomes (good gnomAD genomes coverage = 31.4). The variant is a missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before: alternative variants chr3:178936091G>C (Glu545Gln); chr3:178936092A>C (Glu545Ala); chr3:178936092A>G (Glu545Gly); chr3:178936092A>T (Glu545Val); chr3:178936093G>C (Glu545Asp) and chr3:178936093G>T (Glu545Asp) are classified Pathogenic. The variant is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease: 246 out of 254 non-VUS missense variants in gene PIK3CA are pathogenic = 96.9% which is more than threshold of 51.0%, and 259 out of 587 clinically reported variants in gene PIK3CA are pathogenic = 44.1% which is more than threshold of 12.0%. Multiple lines of computational evidence support a deleterious effect on the gene or gene product: Pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (PMID:30376034). The variant is annotated in Clinvar as a pathogenic variant associated with PIK3CA-related overgrowth spectrum (https://www.ncbi.nlm.nih.gov/clinvar/variation/13655/). Based on a modification of the ACMG Guidelines (PMID:25741868, 25880439), the PIK3CA c.1633G>A; p.(Glu545Lys) variant is classified as a pathogenic variant.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV001092440 SCV002525703 pathogenic not provided 2020-12-09 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, NBK153722 and others). The p.E545K variant substitutes the glutamic acid at position 545 with lysine within the helical domain of the PIK3CA protein. 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 RCV000014631 SCV000034886 pathogenic Breast adenocarcinoma 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014632 SCV000034887 pathogenic OVARIAN CANCER, EPITHELIAL, SOMATIC 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014633 SCV000034888 pathogenic Carcinoma of colon 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014634 SCV000034889 pathogenic Neoplasm of stomach 2012-06-24 no assertion criteria provided literature only
OMIM RCV000038671 SCV000034890 pathogenic Non-small cell lung carcinoma 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014636 SCV000034891 pathogenic Seborrheic keratosis 2012-06-24 no assertion criteria provided literature only
OMIM RCV000055930 SCV000056678 pathogenic Megalencephaly-capillary malformation-polymicrogyria syndrome 2012-06-24 no assertion criteria provided literature only
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000038671 SCV000062349 pathogenic Non-small cell lung carcinoma 2009-05-29 no assertion criteria provided clinical testing
GeneReviews RCV000055930 SCV000086943 pathologic Megalencephaly-capillary malformation-polymicrogyria syndrome 2013-08-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Laboratory of Translational Genomics, National Cancer Institute RCV000119356 SCV000154253 not provided Sarcoma no assertion provided not provided
Database of Curated Mutations (DoCM) RCV000421583 SCV000503934 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431416 SCV000503935 pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438587 SCV000503936 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422210 SCV000503937 pathogenic Neoplasm of ovary 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000038671 SCV000503938 pathogenic Non-small cell lung carcinoma 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441949 SCV000503939 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425490 SCV000503940 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433976 SCV000503941 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441866 SCV000503942 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426520 SCV000503943 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438060 SCV000503944 likely pathogenic Gallbladder carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420851 SCV000503945 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427202 SCV000503946 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437876 SCV000503947 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418058 SCV000503948 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428639 SCV000503949 likely pathogenic Nasopharyngeal neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438445 SCV000503950 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417835 SCV000503951 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429391 SCV000503952 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440053 SCV000503953 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421958 SCV000503954 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432636 SCV000503955 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440694 SCV000503956 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423327 SCV000503957 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433152 SCV000503958 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442569 SCV000503959 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000422210 SCV000924160 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
MAGI's Lab - Research,MAGI Group RCV001327963 SCV001437639 pathogenic Abnormality of cardiovascular system morphology no assertion criteria provided provider interpretation
Institute of Medical Sciences, Banaras Hindu University RCV001374447 SCV001571411 pathogenic Gallbladder cancer 2020-10-30 no assertion criteria provided research
James Bennett Lab,Seattle Childrens Research Institute RCV001730473 SCV001960167 pathogenic Cerebrofacial Vascular Metameric Syndrome (CVMS) 2021-09-30 no assertion criteria provided clinical testing

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