rs121913283
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP5_Very_Strong
The NM_006218.4(PIK3CA):c.3129G>A(p.Met1043Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1043L) 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 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3CA | NM_006218.4 | c.3129G>A | p.Met1043Ile | missense_variant | 21/21 | ENST00000263967.4 | |
PIK3CA | XM_006713658.5 | c.3129G>A | p.Met1043Ile | missense_variant | 21/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3CA | ENST00000263967.4 | c.3129G>A | p.Met1043Ile | missense_variant | 21/21 | 2 | NM_006218.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma 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 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2022 | Identified in patients with features of PIK3CA-related overgrowth and brain malformations spectrum disorder referred for genetic testing at GeneDx and in the published literature (Kuentz et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33745098, 31831300, 22120714, 15930273, 26627007, 28151489) - |
Cowden syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 15930273, 17376864, 22120714). 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) performed at Invitae indicates that this missense variant is expected to disrupt PIK3CA protein function. ClinVar contains an entry for this variant (Variation ID: 179173). This missense change has been observed in individual(s) with hemimegalencephaly (PMID: 28151489). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1043 of the PIK3CA protein (p.Met1043Ile). - |
Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
PIK3CA related overgrowth syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Jan 20, 2015 | - - |
Malignant neoplasm of body of uterus Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of brain Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Non-small cell lung carcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 19, 2013 | The Met1043Ile variant has been identified as a somatic change in tumors from mulitple tissues, including endometrium, lung, cervix, urinary tract and large intestine (COSMIC). - |
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Adenoid cystic carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the head and neck 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 | - - |
Thyroid tumor 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