ClinVar Miner

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

dbSNP: rs121913281
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Total submissions: 36
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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).
Invitae 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; Neoplasm of ovary; 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 RCV001092441 SCV002525571 pathogenic not provided 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 not provided Megalencephaly-capillary malformation-polymicrogyria syndrome 2024-02-26 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 not provided HEMIFACIAL MYOHYPERPLASIA, SOMATIC 2024-02-26 no assertion criteria provided literature only

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