ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This variant has previously been reported in multiple unrelated individuals with a molecular diagnosis of PROS, including those with reported overgrowth and macrodactyly (PMID: 27631024, PMID: 31263565). The p.Glu453Lys variant substitutes the glutamic acid at position 453 with lysine within the C2 phosphatidylinositol 3-kinase domain of the PIK3CA protein (UniProt P42336, aa# 330-487). This is a recurrent hotspot. PIK3CA variants associated with PROS overlap those reported as oncogenic variants found in multiple tumor types (COSMIC and cBioPortal Databases)

A suspected mosaic missense variant was identified, NM_006218.2(PIK3CA):c.1357G>A in exon 8 of the PIK3CA gene. This substitution is predicted to create a minor amino acid change from a glutamic acid to a lysine at position 453 of the protein; NP_006209.2(PIK3CA):p.(Glu453Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located within the C2 domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. This variant has been previously reported as pathogenic in patients with overgrowth disorders (Mirzaa, G. et al . (2016); Piacitelli, A. et al . (2018)). A different variant in the same codon resulting in an inframe deletion has also been shown to cause the same condition (Mirzaa, G. et al . (2016); Riviere, J-B. et al . (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

Published functional studies demonstrate a damaging effect: increased phosphorylation of AKT on serine 473 (Rudd et al., 2011); 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: 23352210, 29759595, 26619011, 21531001, 27834349, 27631024, 30063105, 27037860, 31263565, 21266528)

This variant has been identified by standard clinical testing. somatic mutation

For these reasons, this variant has been classified as Pathogenic. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with PIK3CA-associated overgrowth conditions (PMID: 27631024, 27631024, 28151489, ClinVar). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376470). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 453 of the PIK3CA protein (p.Glu453Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.

A PIK3CA c.1357G>A (p.Glu453Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Mirzaa G et al., PMID: 27631024; Kuentz P et al., PMID: 28151489; McNulty SN et al., PMID: 31585106; Tian W et al., PMID: 33054853; Debelenko L et al., PMID: 36775953; Mojarad BA et al., 2023). This variant has been reported in the ClinVar database as pathogenic in both a somatic and germline state (ClinVar Variation ID: 376470) and it has been reported in numerous cases in the cancer database COSMIC (ID: COSV55874585). This variant is absent from the general population (gnomAD v4.1.0), indicating it is not a common variant. The PIK3CA c.1357G>A (p.Glu453Lys) variant resides within the C2 domain of PIK3CA and is defined as a critical functional domain (Lai et al, PMID: 35997716). The PIK3CA gene is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai et al, PMID: 35997716). Functional studies show that this variant leads to increased AKT phosphorylation on Ser473, indicating that this variant is activating, and thereby promotes increased proliferation of cancer-derived cells in tissue culture (Rudd ML et al., PMID: 21266528; Smit DJ et al., PMID: 38909932). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the PIK3CA c.1357G>A (p.Glu453Lys) variant is classified as pathogenic.

This variant was reported in multiple patients with PIK3CA-associated overgrowth condition (OMIM #602501, PMID 30063105, 22729224). This variant is not present in population database gnomAD (v4.1.0). It has been reported as pathogenic or likely pathogenic in ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.

Variant summary: PIK3CA c.1357G>A (p.Glu453Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 228320 control chromosomes (gnomAD). c.1357G>A has been reported in the literature in multiple individuals affected with PIK3CA-Associated Segmental Overgrowth (Mirzaa_2016, Kuentz_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected the PIK3CA protein function (Burke_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22949682, 27631024, 28151489). ClinVar contains an entry for this variant (Variation ID: 376470). Based on the evidence outlined above, the variant was classified as pathogenic.