Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000482573 | SCV000565880 | pathogenic | not provided | 2022-11-18 | criteria provided, single submitter | clinical testing | Identified in heterozygous and mosaic states in other unrelated patients with features of PIK3CA-related overgrowth and brain malformations spectrum disorder referred for genetic testing at GeneDx and in published literature (McDermott et al., 2018; Mirzaa et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27631024, 35357905, 31699932, 33077954, 34652076, 29895132, 28941273) |
| Clinical Genetics and Genomics, |
RCV000482573 | SCV001450157 | likely pathogenic | not provided | 2015-10-21 | criteria provided, single submitter | clinical testing | |
| Care4Rare- |
RCV003233647 | SCV003932118 | pathogenic | PIK3CA related overgrowth syndrome | criteria provided, single submitter | research | ||
| Clinical Genomics Laboratory, |
RCV003233647 | SCV005049523 | pathogenic | PIK3CA related overgrowth syndrome | 2023-12-18 | criteria provided, single submitter | clinical testing | A PIK3CA c.1048G>A (p.Asp350Asn) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in three individuals with PIK3CA-Related Overgrowth Spectrum Disorder (PROS) (Nasomyont N et al., PMID: 37908459; McDermott JH et al., PMID: 28941273; Mirzaa G et al., PMID: 27631024) as well as in numerous cases in the cancer database COSMIC (COSMIC ID: COSV55892795). The PIK3CA c.1048G>A (p.Asp350Asn) has been reported in the ClinVar database as a germline likely pathogenic/pathogenic variant by two submitters (ClinVar ID: 418658). It is absent from the general population (gnomAD v.4.0.0), indicating it is not a common variant. This variant resides within a region, the C2 domain, of PIK3CA that is defined as a critical functional domain (Lai A et al., PMID: 35997716). Functional studies show that the p.Asp350Asn variant results in increased transformation ability in two different cell lines in culture (Ng PK et al., PMID: 29533785), and therefore, is predicted to lead to a gain of protein function. Another variant in the same codon, c.1049A>G (p.Asp350Gly), has been reported in ClinVar in a germline state and is considered pathogenic (ClinVar ID: 521363), and has also been identified as a somatic variant in numerous cancer types in COSMIC (COSMIC ID: COSV55877939). 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. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the PIK3CA c.1048G>A (p.Asp350Asn) variant is classified as pathogenic. |
| Yale Center for Mendelian Genomics, |
RCV001849378 | SCV002106925 | likely pathogenic | Megalencephaly-capillary malformation-polymicrogyria syndrome | 2020-10-19 | no assertion criteria provided | literature only |