ClinVar

Description

A somatic mutation is present within the PIK3CA (Exon 10) gene in the DNA extracted from tissue. Gain-of-function (usually somatic mosaic) mutations in PIK3CA are associated with PIK3CA-Related Overgrowth Spectrum (PROS) and the PIK3CA c.1633G>A; p.(Glu545Lys) (Chr3:g.178936091G>A) variant has previously been reported in patients with PROS, CLOVES syndrome, fibroadipose hyperplasia and isolated macrodactyly (PMID: 28151489, 29661094) The PIK3CA c.1633G>A; p.(Glu545Lys) variant results in a p110 alpha-helical domain substitution (PMID:26637981), activates AKT, disrupts normal EC-characteristic monolayer morphology as visualized by phase-contrast microscopy, results in loss of ECM fibronectin, and strongly downregulates ANGPT2 and PDGF-B mRNA expression as measured by real-time quantitative PCR. Plasminogen system-components are also somewhat dysregulated by the variant PIK3CA c.1633G>A; p.(Glu545Lys) (PMID:26637981). The variant is located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation: using strength Strong because Hot-spot of length 17 amino-acids has 21 non-VUS missense/in-frame variants (21 pathogenic and 0 benign), pathogenicity = 100.0%, qualifies as a dense hot-spot. The variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium: GnomAD exomes allele count = 1 is less than 5 for gene PIK3CA (good gnomAD exomes coverage = 42.7) and the variant is not found in gnomAD genomes (good gnomAD genomes coverage = 31.4). The variant is a missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before: alternative variants chr3:178936091G>C (Glu545Gln); chr3:178936092A>C (Glu545Ala); chr3:178936092A>G (Glu545Gly); chr3:178936092A>T (Glu545Val); chr3:178936093G>C (Glu545Asp) and chr3:178936093G>T (Glu545Asp) are classified Pathogenic. The variant is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease: 246 out of 254 non-VUS missense variants in gene PIK3CA are pathogenic = 96.9% which is more than threshold of 51.0%, and 259 out of 587 clinically reported variants in gene PIK3CA are pathogenic = 44.1% which is more than threshold of 12.0%. Multiple lines of computational evidence support a deleterious effect on the gene or gene product: Pathogenic computational verdict based on 11 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 1 benign prediction from MutationAssessor (PMID:30376034). The variant is annotated in Clinvar as a pathogenic variant associated with PIK3CA-related overgrowth spectrum (https://www.ncbi.nlm.nih.gov/clinvar/variation/13655/). Based on a modification of the ACMG Guidelines (PMID:25741868, 25880439), the PIK3CA c.1633G>A; p.(Glu545Lys) variant is classified as a pathogenic variant.