ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg)

dbSNP: rs121913279
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Total submissions: 62
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Brain Malformations Variant Curation Expert Panel RCV001836707 SCV001949970 pathogenic Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 2022-02-11 reviewed by expert panel curation The c.3140A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.His1047Arg). This variant is present in one individual in gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; PMIDs: 27191687, 28328134, 25292196, 22729222, 25424831, 465 entries in COSMIC, Segmental overgrowth or vascular malformation of a limb or region of the body, present in patient derived cell lines). 60 independent Ba/F3 and 57 independent MCF10A experiments showed this variant has a proliferative effect indicating that this variant impacts protein function (PMID:29533785 ) (PS3_Moderate). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_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). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25424831). 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: PM2_P, PS4_VS, PS3_M, PM1_P, PP2, PS2_M; 15 points (VCEP specifications version 1; Approved: 1/31/2021)
Donald Williams Parsons Laboratory, Baylor College of Medicine RCV000487449 SCV000292259 pathogenic Rosette-forming glioneuronal tumor criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000024621 SCV000803841 pathogenic CLOVES syndrome criteria provided, single submitter clinical testing
Biesecker Lab Rare Disease, National Institutes of Health RCV000201231 SCV000898478 pathogenic PIK3CA related overgrowth syndrome 2019-04-19 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001092442 SCV001248958 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000024621 SCV001428754 pathogenic CLOVES syndrome 2019-11-11 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001092442 SCV001446687 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526648 SCV001737079 pathogenic Congenital macrodactylia criteria provided, single submitter clinical testing
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz RCV001705590 SCV001934209 pathogenic Segmental undergrowth associated with lymphatic malformation 2021-04-06 criteria provided, single submitter clinical testing
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz RCV001705589 SCV001934211 pathogenic Segmental undergrowth associated with mainly venous malformation with capillary component 2021-04-06 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001729349 SCV001976965 pathogenic CLAPO syndrome 2021-10-01 criteria provided, single submitter clinical testing PS3, PM1, PM2, PM5, PP2, PP3, PP4, PP5
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001092442 SCV002009609 likely pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV001807727 SCV002059601 pathogenic Megalencephaly-capillary malformation-polymicrogyria syndrome 2021-02-12 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV001092442 SCV002061476 pathogenic not provided 2021-08-05 criteria provided, single submitter clinical testing PS4, PS3, PM2
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV001092442 SCV002525705 pathogenic not provided 2020-09-20 criteria provided, single submitter clinical testing This variant substitutes the histidine with arginine at position 1047 within the PIK3CA kinase domain. This is a recurrent pathogenic variant. Several unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the somatic activating PIK3CA p.His1047Arg variant have previously been reported (PMID: 25681199, PMID: 26637981, PMID: 24903541, PMID: 30180809, PMID: 28328134 and others).
GeneDx RCV001092442 SCV002559314 pathogenic not provided 2022-08-03 criteria provided, single submitter clinical testing Reported as a somatic variant in various tumor samples (Campbell et al., 2004; Li et al., 2005); Published functional studies demonstrate increased lipid kinase activity and transforming activities, and a mouse model with this variant demonstrated increased body weight, increased organ size, and severe metabolic defects (Ikenoue et al., 2005; Kinross et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16322209, 15289301, 15016963, 25599672, 23100325, 25550458, 15930273, 16432179, 19805105, 21708979, 15520168, 15784156, 27631024, 24903541, 22658544, 32770747, 34568242, 34075207)
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust RCV003325939 SCV003853395 pathogenic Klippel-Trenaunay-like-Syndrome 2023-03-23 criteria provided, single submitter clinical testing
OMIM RCV000014622 SCV000034877 pathogenic Breast adenocarcinoma 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014623 SCV000034878 pathogenic OVARIAN CANCER, EPITHELIAL, SOMATIC 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014624 SCV000034879 pathogenic Carcinoma of colon 2012-06-24 no assertion criteria provided literature only
OMIM RCV002508124 SCV000034880 pathogenic Gastric cancer 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014626 SCV000034881 pathogenic Hepatocellular carcinoma 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014627 SCV000034882 pathogenic Non-small cell lung carcinoma 2012-06-24 no assertion criteria provided literature only
OMIM RCV000014628 SCV000034883 pathogenic Seborrheic keratosis 2012-06-24 no assertion criteria provided literature only
OMIM RCV000024621 SCV000050487 pathogenic CLOVES syndrome 2012-06-24 no assertion criteria provided literature only
GeneReviews RCV000024621 SCV000086944 not provided CLOVES syndrome no assertion provided literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000014627 SCV000199905 pathogenic Non-small cell lung carcinoma 2010-08-05 no assertion criteria provided clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154516 SCV000204187 pathogenic Neoplasm of ovary 2010-08-05 no assertion criteria provided clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis RCV000201231 SCV000255984 pathogenic PIK3CA related overgrowth syndrome 2015-04-01 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000432506 SCV000504107 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442164 SCV000504108 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425956 SCV000504109 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436234 SCV000504110 pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000014627 SCV000504111 pathogenic Non-small cell lung carcinoma 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426498 SCV000504112 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437153 SCV000504113 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419938 SCV000504114 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430589 SCV000504115 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437782 SCV000504116 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420562 SCV000504117 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431232 SCV000504118 likely pathogenic Adrenal cortex carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438435 SCV000504119 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000154516 SCV000504120 pathogenic Neoplasm of ovary 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428372 SCV000504121 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000014626 SCV000504122 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421855 SCV000504123 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432543 SCV000504124 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442736 SCV000504125 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422442 SCV000504126 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433127 SCV000504127 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443546 SCV000504128 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426614 SCV000504129 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437287 SCV000504130 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442731 SCV000504131 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
OMIM RCV000709691 SCV000839591 pathogenic MACRODACTYLY, SOMATIC 2012-06-24 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000154516 SCV000923968 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Institute of Medical Sciences, Banaras Hindu University RCV001255686 SCV001432251 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research
MAGI's Lab - Research, MAGI Group RCV001327968 SCV001437644 pathogenic Abnormal cardiovascular system morphology no assertion criteria provided provider interpretation
James Bennett Lab, Seattle Childrens Research Institute RCV001730472 SCV001960168 pathogenic Cerebrofacial Vascular Metameric Syndrome (CVMS) 2021-09-30 no assertion criteria provided clinical testing
OMIM RCV001728091 SCV001976535 pathogenic CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC 2012-06-24 no assertion criteria provided literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein RCV000024621 SCV002583480 pathogenic CLOVES syndrome 2022-06-02 no assertion criteria provided clinical testing
Medical Oncology, Institut Jules Bordet RCV003128082 SCV003803732 pathogenic Breast carcinoma no assertion criteria provided clinical testing

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