Submissions for variant NM_006218.4(PIK3CA):c.323G>A (p.Arg108His)

gnomAD frequency: 0.00001  dbSNP: rs886042002

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000404833	SCV000330828	pathogenic	not provided	2023-05-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, specifically, R108H increased the phosphorylation levels of downstream elements in U2OS transfected cells, as compared to wild-type (Oda et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18829572, 26749308, 28247034, 30243889, 35282043, 34402524, 34854542)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195259	SCV001365567	uncertain significance	not specified	2019-09-20	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg108His variant in PIK3CA has been previously identified as a de novo mosaic variant in one individual with overgrowth, macrocephaly, meningioma, syndactyly, missing teeth, umbilical hernia, and dysmorphic features; and one individual with macrocephaly, speech delay, laryngeal cleft, polychondritis, and Chiari I malformation (GeneDx pers. comm.; ClinVar Variation ID 280875). The variant also reportedly occurred de novo in one individual with macrocephaly and autism (Turner 2016). None of these individuals were reported to have capillary malformations or other typical cutaneous manifestations of PIK3CA-related disease. The p.Arg108His variant is also a frequent somatic finding in mutliple cancer types (COSMIC database; https://cancer.sanger.ac.uk/cosmic/). It was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg108His variant is uncertain uncertain due to limited evidence including the lack of a consistent phenotype in the reported probands. ACMG/AMP Criteria applied: PS2_Moderate, PM2.
Johns Hopkins Genomics, Johns Hopkins University	RCV001353357	SCV001548510	likely pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2021-03-26	criteria provided, single submitter	clinical testing	This missense variant in PIK3CA is absent from a large population database and has an entry in ClinVar. It has been reported in the literature as a de novo change in an individual with macrocephaly and autism. Three bioinformatic tools queried predict that this substitution would be damaging, but these algorithms have low specificity, especially for predicting gain-of-function variants. In vitro functional studies of Arg108His indicate increased phosphorylation levels of downstream P13K singalling targets, suggesting a gain-of-function mechanism. The arginine residue at this position is strongly conserved across all vertebrate species assessed. This variant is not predicted to effect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. The allelic fraction of MCAP-associated variants in PIK3CA range from 10-50% but vary widely across different tissue types. We consider c.323G>A to be likely pathogenic.
Invitae	RCV001859541	SCV002170438	likely pathogenic	Cowden syndrome	2022-07-29	criteria provided, single submitter	clinical testing	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"). ClinVar contains an entry for this variant (Variation ID: 280875). This missense change has been observed in individuals with clinical features of PIK3CA-related overgrowth spectrum (PMID: 26749308, 34402524; Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 108 of the PIK3CA protein (p.Arg108His). Experimental studies have shown that this missense change affects PIK3CA function (PMID: 18829572). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV002287404	SCV002577867	likely pathogenic	See cases	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP2,PP3
Illumina Laboratory Services, Illumina	RCV001353357	SCV004014727	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The PIK3CA c.323G>A (p.Arg108His) missense variant results in the substitution of arginine at amino acid position 108 with histidine. This variant has been reported in a heterozygous state in three individuals with features of PIK3CA-related overgrowth spectrum, including macrocephaly, developmental delay, syndactyly, and vascular tumor (PMID: 26749308; PMID: 34854542; PMID: 34402524). The variant was mosaic in two of the individuals, and it has also been reported as a somatic mutation in multiple tumor samples in the COSMIC database (COSM27497). The c.323G>A variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000015 in the European (non-Finnish) population (version 3.1.2). This variant is located in the p85 binding domain of PIK3CA and assays of phosphorylation of downstream targets of PI3K in osteosarcoma cells have confirmed the variant results in a gain-of-function (PMID: 18829572). This variant was identified in a de novo state. Based on the available evidence, the c.323G>A (p.Arg108His) variant is classified as pathogenic for PIK3CA-related overgrowth spectrum.