Submissions for variant NM_006218.4(PIK3CA):c.263G>A (p.Arg88Gln)

dbSNP: rs121913287

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224952	SCV001397182	pathogenic	Cowden syndrome	2019-05-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to have conflicting or insufficient data to determine the effect on PIK3CA protein function (PMID: 22949682). This variant has been observed in individuals affected with megalencephaly-capillary malformation syndrome, including (PMID: 22729224, 28941273). In at least one of these individuals, the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 376049). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 88 of the PIK3CA protein (p.Arg88Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
GeneDx	RCV001562650	SCV001785447	pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Identified in a patient with a clinical diagnosis of megalencephaly-capillary malformation with recurrent ketotic hypoglycemia in published literature (McDermott et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22729224, 28941273)
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002274026	SCV002558895	pathogenic	PIK3CA related overgrowth syndrome		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225067	SCV003921913	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Cowden syndrome 5 (MIM#615108) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) (MIM#602501). (I) 0107 - This gene is associated with autosomal dominant disease. In addition, MCAP is often associated with post-zygotic mosaicism (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in gnomAD). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in MCAP patients, and in most cases, was de novo and confirmed to be a result of post-zygotic mosaicism. It has also been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 22729224, 29296277, 28941273, 32778138). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomic Medicine Lab, University of California San Francisco	RCV003995942	SCV004847153	pathogenic	Cowden syndrome 5	2023-02-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003225067	SCV005200389	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2024-08-30	criteria provided, single submitter	clinical testing	mosaic
CeGaT Center for Human Genetics Tuebingen	RCV001562650	SCV005909869	pathogenic	not provided	2025-03-01	criteria provided, single submitter	clinical testing	PIK3CA: PS2:Very Strong, PM2, PS4:Moderate
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785354	SCV000923922	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Diagnostic Laboratory, Strasbourg University Hospital	RCV002275002	SCV002562836	pathogenic	Abnormal cerebral morphology		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV004767253	SCV005091335	likely pathogenic	CLOVES syndrome	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team