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

dbSNP: rs104886003

Total submissions: 53

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001092440	SCV001248954	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PIK3CA: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP4
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 syndrome	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	2023-01-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as E545K causes constitutive AKT phosphorylation and increases lipid kinase activity compared to wildtype (Ikenoue et al., 2005; Limaye et al., 2015); 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: 15950905, 24080956, 29152088, 27317099, 25599672, 22729223, 23946963, 17376864, 16432179, 26637981, 27631024, 28425981, 30341384, 30547809, 32901329, 15930273, 22729224)
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	RCV004698419	SCV002525703	pathogenic	PIK3CA overgrowth syndrome	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).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001290591	SCV004176947	pathogenic	PIK3CA related overgrowth syndrome	2023-11-01	criteria provided, single submitter	clinical testing	The PIK3CA c.1633G>A (p.Glu545Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in numerous individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Yeung KS et al., PMID: 28328134; Mirzaa G et al., PMID: 27631024; Keppler-Noreuil KM et al., PMID: 25557259; Keppler-Noreuil KM et al., PMID: 24782230; McNulty SN et al., PMID: 31585106; Luks VL et al., PMID: 25681199; Jansen LA et al., PMID: 25722288; Piacitelli AM et al., PMID: 30063105). It has been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55873239), and it has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters in both a germline and somatic state (ClinVar ID: 13655). Another variant in the same codon, PIK3CA c.1634A>C (p.Glu545Ala), has been reported in individuals with lymphatic malformation and is considered pathogenic (Osborn AJ et al., PMID: 25292196; ClinVar ID: 13659). The PIK3CA c.1633G>A (p.Glu545Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. 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; Keppler-Noreuil KM et al., PMID: 25557259; Gymnopoulos M et al., PMID: 17376864). Computational predictors indicate that the PIK3CA c.1633G>A (p.Glu545Lys) variant is damaging, evidence that correlates with impact on PIK3CA function. In support of this prediction, functional in vitro and patient-derived cell studies show that this lysine substitution at codon 545 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling (Gymnopoulos M et al., PMID: 17376864; Menteş M et al. PMID: 35842959). Additionally, the PIK3CA gene 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 (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.1633G>A (p.Glu545Lys) variant is classified as pathogenic.
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	RCV002508125	SCV000034889	pathogenic	Gastric cancer	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	not provided	Megalencephaly-capillary malformation-polymicrogyria syndrome		no assertion provided	literature only
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	Ovarian neoplasm	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	Papillary renal cell carcinoma type 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	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MAGI's Lab - Research, MAGI Group	RCV001327963	SCV001437639	pathogenic	Abnormal 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
OMIM	RCV003764575	SCV004697481	pathogenic	HEMIFACIAL MYOHYPERPLASIA, SOMATIC	2012-06-24	no assertion criteria provided	literature only
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527294	SCV005038940	likely pathogenic	Rare venous malformation	2024-03-19	no assertion criteria provided	clinical testing
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527295	SCV005038941	likely pathogenic	Rare combined vascular malformation	2024-03-19	no assertion criteria provided	clinical testing
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527293	SCV005038942	likely pathogenic	Angioosteohypertrophic syndrome	2024-03-19	no assertion criteria provided	clinical testing