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

dbSNP: rs121913281

Total submissions: 36

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	2023-10-13	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). Advanced 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 at Invitae 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	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.
OMIM	RCV000032909	SCV000056681	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2012-06-24	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425809	SCV000504943	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436090	SCV000504944	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418438	SCV000504945	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425119	SCV000504946	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435399	SCV000504947	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417782	SCV000504948	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428005	SCV000504949	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441716	SCV000504950	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420550	SCV000504951	likely pathogenic	Malignant tumor of floor of mouth	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430750	SCV000504952	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441028	SCV000504953	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423369	SCV000504954	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433635	SCV000504955	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440398	SCV000504956	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422744	SCV000504957	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432906	SCV000504958	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442782	SCV000504959	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425540	SCV000504960	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432323	SCV000504961	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441963	SCV000504962	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424877	SCV000504963	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435124	SCV000504964	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444680	SCV000504965	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
OMIM	RCV003882732	SCV004697537	pathogenic	HEMIFACIAL MYOHYPERPLASIA, SOMATIC	2012-06-24	no assertion criteria provided	literature only