Submissions for variant NM_006218.4(PIK3CA):c.3140A>T (p.His1047Leu)

dbSNP: rs121913279

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626894	SCV000747597	pathogenic	Macrodactyly of toe; Stroke disorder	2017-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000987367	SCV001136646	pathogenic	Cowden syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253236	SCV001428854	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2018-11-07	criteria provided, single submitter	clinical testing	This variant was identified as de novo
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526597	SCV001737026	pathogenic	Hemihypertrophy		criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001807728	SCV002059602	pathogenic	Colorectal cancer	2020-04-02	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002254265	SCV002525712	pathogenic	not provided	2021-04-27	criteria provided, single submitter	clinical testing	This variant has previously been reported in numerous unrelated individuals with PIK3CA-related segmental overgrowth syndrome, including individuals with venous malformations (PMID: 25681199, PMID: 27631024, PMID: 28151489, NBK153722). The p.H1047L variant substitutes the histidine with leucine at position 1047 within the PIK3CA kinase domain. This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 26627007).
Ambry Genetics	RCV004649064	SCV005153737	pathogenic	Inborn genetic diseases	2024-06-18	criteria provided, single submitter	clinical testing	The c.3140A>T (p.H1047L) alteration is located in exon 21 (coding exon 20) of the PIK3CA gene. This alteration results from an A to T substitution at nucleotide position 3140, causing the histidine (H) at amino acid position 1047 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/248274) total alleles studied. The highest observed frequency was 0.001% (1/112236) of European (non-Finnish) alleles. This variant was reported in multiple individuals with features consistent with PIK3CA-related disorders (Lindhurst, 2012; Luks, 2015; Sasaki, 2023). Another alteration at the same codon, c.3140A>G (p.H1047R), has also been detected in multiple individuals with features consistent with PIK3CA-related disorders (Pagliazzi, 2021; Delgado-Miguel, 2021; Rios, 2013; Lindhurst, 2012; Kurek, 2012; Mirzaa, 2016; D'Gama, 2015). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In vitro studies demonstrated the variant to have increased growth-promoting activity and exhibit robust activation of the PI3K/AKT/mTOR pathway (Dogruluk, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000014629	SCV000034884	pathogenic	Breast adenocarcinoma	2012-06-24	no assertion criteria provided	literature only
OMIM	RCV000032905	SCV000056677	pathogenic	CLOVES syndrome	2012-06-24	no assertion criteria provided	literature only
GeneReviews	RCV000032905	SCV000086945	not provided	CLOVES syndrome		no assertion provided	literature only
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000201235	SCV000255986	pathogenic	PIK3CA related overgrowth syndrome	2014-11-25	no assertion criteria provided	clinical testing
OMIM	RCV000709692	SCV000839592	pathogenic	CLAPO syndrome	2012-06-24	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000422323	SCV000923937	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
OMIM	RCV001728092	SCV001976536	pathogenic	CEREBRAL CAVERNOUS MALFORMATIONS 4, SOMATIC	2012-06-24	no assertion criteria provided	literature only
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527292	SCV005038931	likely pathogenic	Cavernous lymphangioma	2024-03-19	no assertion criteria provided	clinical testing