Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000038672 | SCV000062350 | pathogenic | Ovarian neoplasm | 2010-08-10 | criteria provided, single submitter | clinical testing | |
| Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV002254273 | SCV002525570 | pathogenic | not provided | 2021-02-04 | criteria provided, single submitter | clinical testing | This variant has previously been reported in multiple unrelated individuals with PIK3CA-related segmental overgrowth syndrome (PMID: 25681199, PMID: 31585106). Phenotypic information was limited in the majority of cases, but one individual had a clinical diagnosis of Fibro-Adipose Vascular Anomaly (FAVA) (PMID: 25681199). PIK3CA variants associated with PROS, including this patient's alteration, overlap those reported as oncogenic variants found in multiple tumor types (cBioPortal and NCI's Genomic Data Commons cancer databases). The p.Gln546Arg replaces the glutamine at codon 546 with arginine within the helical domain of the PIK3CA protein (UniProt P42336). Experimental studies have demonstrated that the p.Gln546Arg variant causes overactivation of the PI3K/AKT/mTOR pathway and increased proliferation in vitro (PMID: 26627007). |
| Clinical Genomics Laboratory, |
RCV003458193 | SCV004176941 | pathogenic | PIK3CA related overgrowth syndrome | 2023-08-09 | criteria provided, single submitter | clinical testing | A PIK3CA c.1637A>G (p.Gln546Arg) variant was identified at an allelic fraction consistent with somatic origin. The PIK3CA c.1637A>G (p.Gln546Arg) variant has been reported in multiple individuals affected with PROS disorders, including patients with lymphatic malformations (Kuentz P et al., PMID: 28151489; Piacitelli AM et al., PMID: 30063105; Parker VER et al., PMID: 30270358; McNulty SN et al., PMID: 31585106; Brouillard P et al., PMID: 34112235). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic by multiple submitters (ClinVar Variation ID: 54633). It has also been reported in multiple cases in the cancer database COSMIC (Genomic Mutation ID: COSV55876869). The PIK3CA c.1637A>G (p.Gln546Arg) variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors suggest that this variant may have a deleterious impact on the structure and/or function of the PIK3CA-encoded protein. Functional studies show p.Gln546Arg to be activating, as demonstrated by increased transformation ability in multiple cell lines (Dogruluk T et al., PMID: 26627007; Ng PK et al., PMID: 29533785). Multiple variants in the same codon, p.Gln546Glu, p.Gln546His, p.Gln546Leu, p.Gln546Lys, and p.Gln546Pro, have been reported and are considered pathogenic (ClinVar Variation IDs: 13654, 376491, 375899, 13657, 375898). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.1637A>G (p.Gln546Arg) variant is classified as pathogenic. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000038672 | SCV000923960 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research | |
| MAGI's Lab - |
RCV001327965 | SCV001437641 | pathogenic | Abnormal cardiovascular system morphology | no assertion criteria provided | provider interpretation |