Submissions for variant NM_006218.4(PIK3CA):c.3139C>T (p.His1047Tyr)

dbSNP: rs121913281

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038675	SCV000062353	pathogenic	Non-small cell lung carcinoma	2011-03-01	criteria provided, single submitter	clinical testing	This variant has been observed and confirmed as a somatic variant in large intestine, endometrium, breast and ovarian tumors (COSMIC). Somatic PIK3CA variants have been identified in up to 4% of cases of lung cancer (Samuels 2004).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698423	SCV000827084	pathogenic	Cowden syndrome	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1047 of the PIK3CA protein (p.His1047Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome (PMID: 22729224, 27631024). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39705). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 17376864). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763508	SCV000894305	pathogenic	Familial cancer of breast; Megalencephaly-capillary malformation-polymicrogyria syndrome; Lung carcinoma; Congenital macrodactylia; Seborrheic keratosis; Epidermal nevus; Ovarian neoplasm; CLAPO syndrome; CLOVES syndrome; Carcinoma of colon; Neoplasm of stomach; Cowden syndrome 5; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092441	SCV001248957	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz	RCV001705625	SCV001934212	pathogenic	Segmental undergrowth associated with mainly venous malformation with capillary component	2021-04-06	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000032909	SCV002012071	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with stron evidence (ClinVar ID: VCV000039705.10, PS1).The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.His1047Leu) has been reported as pathogenic (VCV000013653.15 PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.900, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Developmental Brain Disorders Lab, Seattle Children's Hospital	RCV000032909	SCV002104174	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2022-03-08	criteria provided, single submitter	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV002226661	SCV002505775	pathogenic	CLOVES syndrome	2021-08-01	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV004698336	SCV002525571	pathogenic	PIK3CA overgrowth syndrome	2020-11-30	criteria provided, single submitter	clinical testing	This variant substitutes the histidine with tyrosine at position 1047 within the PIK3CA kinase domain. This is a recurrent pathogenic variant. Multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the somatic activating PIK3CA p.His1047Tyr variant have previously been reported (PMID: 28151489, PMID: 27631024, PMID: 22729224). Further supporting pathogenicity, different missense changes at the same residue (p.His1047Arg, p.His1047Leu, and p.His1047Gln) have been classified as pathogenic (PMID: 25681199, PMID: 28328134 and others).
Care4Rare-SOLVE, CHEO	RCV003233079	SCV003932119	pathogenic	PIK3CA related overgrowth syndrome		criteria provided, single submitter	research
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003233079	SCV004176925	pathogenic	PIK3CA related overgrowth syndrome	2023-10-11	criteria provided, single submitter	clinical testing	A PIK3CA c.3139C>T (p.His1047Tyr) variant was identified at an allelic fraction consistent with somatic origin. The PIK3CA c.3139C>T (p.His1047Tyr) variant has been reported in multiple individuals affected with PROS disorders (Parker VER et al., PMID: 30270358; McNulty SN et al., PMID: 31585106; Gökpınar İli E et al., PMID: 35238469; Chen WL et al., PMID: 35483878; Tian W et al., PMID: 33054853). This variant has been reported in the ClinVar database as pathogenic by multiple submitters (ClinVar ID: 39705) and has been reported in multiple cancer cases in the cancer database COSMIC (COSMIC ID: COSV55876499). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the kinase domain, amino acids 765-1051, of PIK3CA, which is defined as a critical functional domain (Zhao L et al., PMID: 18268322). Functional studies show increased phosphorylation and increased transforming ability, indicating that this variant impacts protein function (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene is defined by the ClinGen's 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). 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.3139C>T (p.His1047Tyr) variant is classified as pathogenic.
Ambry Genetics	RCV004955262	SCV005468933	pathogenic	Inborn genetic diseases	2024-07-23	criteria provided, single submitter	clinical testing	The c.3139C>T (p.H1047Y) alteration is located in exon 21 (coding exon 20) of the PIK3CA gene. This alteration results from a C to T substitution at nucleotide position 3139, causing the histidine (H) at amino acid position 1047 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in two individuals in a megalencephaly-capillary malformation cohort (Rivière, 2012). This variant was also identified as mosaic in other individuals with segmental overgrowth, leg length discrepancy, macrodactyly, vascular malformation, congenital lipomatous truncal overgrowth, and other clinical features consistent with PIK3CA-related disorders (Mirzaa, 2016; Tian, 2020; Chen, 2022). Two other alterations at the same codon, c.3140A>G (p.H1047R) and c.3140A>T (p.H1047L), have been detected in individuals with macrodactyly, congenital progressive segmental overgrowth, lower limb discrepancy, and/or capillaro-lymphatico-venous malformation (Lindhurst, 2012; Sasaki, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV001092441	SCV005628328	pathogenic	not provided	2024-07-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that H1047Y is associated with higher phosphorylation levels of Akt and S6K than wild type, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 17376864); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22729224, 32778138, 32019278, 34322384, 30547809, 33054853, 33057194, 35982159, 37452404, 17376864)
OMIM	RCV000032909	SCV000056681	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2012-06-24	no assertion criteria provided	literature only
OMIM	RCV003882732	SCV004697537	pathogenic	HEMIFACIAL MYOHYPERPLASIA, SOMATIC	2012-06-24	no assertion criteria provided	literature only