chr3-179218305-G-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_006218.4(PIK3CA):c.1635G>T(p.Glu545Asp) variant causes a missense change. 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E545G) 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 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3CA | NM_006218.4 | c.1635G>T | p.Glu545Asp | missense_variant | 10/21 | ENST00000263967.4 | |
PIK3CA | XM_006713658.5 | c.1635G>T | p.Glu545Asp | missense_variant | 10/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3CA | ENST00000263967.4 | c.1635G>T | p.Glu545Asp | missense_variant | 10/21 | 2 | NM_006218.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 24, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (ClinVar ID: VCV000217293.1, PMID:27631024, 32778138, 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.Glu545Lys) has been reported as pathogenic (VCV000013655.18 PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Patient’s phenotype is considered as compatible with Megalencephaly-capillary malformation-polymicrogyria syndrome (PP4_P).Therefore, this variant is classified as likley pathogenic according to the recommendation of ACMG/AMP guideline. - |
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Prostate adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Carcinoma of esophagus 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 | - - |
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 | May 21, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217293). This missense change has been observed in individual(s) with PIK3CA-related overgrowth spectrum (PMID: 27631024, 32778138). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 545 of the PIK3CA protein (p.Glu545Asp). - |
Brainstem glioma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Nasopharyngeal neoplasm 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 | - - |
Hepatocellular 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 | - - |
Small cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Papillary renal cell carcinoma, sporadic Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Capillary malformation Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | - - |
Papillary renal cell carcinoma type 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Ovarian serous cystadenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Uterine carcinosarcoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
PIK3CA related overgrowth syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Oct 17, 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 | - - |
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gallbladder carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of uterine cervix 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 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at