rs121913286
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5
The NM_006218.4(PIK3CA):c.1636C>A(p.Gln546Lys) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q546E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006218.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3CA | NM_006218.4 | c.1636C>A | p.Gln546Lys | missense_variant | 10/21 | ENST00000263967.4 | |
PIK3CA | XM_006713658.5 | c.1636C>A | p.Gln546Lys | missense_variant | 10/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3CA | ENST00000263967.4 | c.1636C>A | p.Gln546Lys | 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
Ovarian neoplasm Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Dec 28, 2021 | This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 32350708 and others). The p.Gln546Lys variant substitutes the glutamate at position 546 with lysine within the PIK helical domain of the PIK3CA protein (UniProt P42336). This is an activating mutation that results in ligand-independent activation of the PI3K-AKT-mTOR pathway and increased proliferation in vitro (PMID: 26627007). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2019 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database in individuals with PIK3CA-related disorders (Stenson et al., 2014); Has not been previously published in association with PIK3CA-related neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 16930767, 19272638, 19394761, 18221484, 26339434, 31536475, 30591517, 25681199, 27307077, 28453743, 29786783, 29985963) - |
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 | - - |
Segmental undergrowth associated with mainly venous malformation with capillary component Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical and Molecular Genetics, Hospital Universitario La Paz | Apr 06, 2021 | - - |
Lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
OVARIAN CANCER, EPITHELIAL, SOMATIC Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
Medulloblastoma 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
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Dec 01, 2014 | - - |
Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
Malignant neoplasm of body of uterus 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 | - - |
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 | - - |
Malignant tumor of prostate Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, University of Tampere | - | - - |
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
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