rs121913272
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_006218.4(PIK3CA):c.1258T>C(p.Cys420Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C420G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006218.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3CA | NM_006218.4 | c.1258T>C | p.Cys420Arg | missense_variant | 8/21 | ENST00000263967.4 | |
PIK3CA | XM_006713658.5 | c.1258T>C | p.Cys420Arg | missense_variant | 8/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3CA | ENST00000263967.4 | c.1258T>C | p.Cys420Arg | missense_variant | 8/21 | 2 | NM_006218.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
CLAPO syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PS1, PM1, PM2, PM5, PP2, PP3, PP5 - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Feb 01, 2022 | - - |
CLOVES syndrome Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2012 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Feb 23, 2021 | This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome, including isolated lymphatic malformation (PMID: 25681199). PIK3CA variants associated with PROS, including this patient's alteration, overlap those reported as oncogenic variants found in multiple tumor types (cBioPortal and NCI's Genomic Data Commons cancer databases). The p.Cys420Arg replaces the cysteine at codon 420 with arginine within the C2 domain of the PIK3CA protein (UniProt P42336). Experimental studies have demonstrated that the p.Cys240Arg variant causes overactivation of the PI3K/AKT/mTOR pathway and increased proliferation in vitro (PMID: 26627007). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | PIK3CA: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP4, PS3:Supporting - |
Ovarian neoplasm Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 08, 2010 | - - |
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Prostate adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Segmental undergrowth associated with lymphatic malformation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical and Molecular Genetics, Hospital Universitario La Paz | Apr 06, 2021 | - - |
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Capillary malformation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Squamous cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Cowden syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 420 of the PIK3CA protein (p.Cys420Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PIK3CA-related overgrowth syndrome (PMID: 22658544, 24782230; Invitae). ClinVar contains an entry for this variant (Variation ID: 31945). 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: 15930273, 17376864, 18074223, 22120714, 22949682). For these reasons, this variant has been classified as Pathogenic. - |
PIK3CA related overgrowth syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Apr 23, 2014 | - - |
Malignant neoplasm of body of uterus Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Abnormal cardiovascular system morphology Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | MAGI's Lab - Research, MAGI Group | - | - - |
Rare combined vascular malformation Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Institute of Tissue Medicine and Pathology, University of Bern | Mar 19, 2024 | - - |
Adenoid cystic carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at