Submissions for variant NM_006218.4(PIK3CA):c.325GAA[1] (p.Glu110del)

dbSNP: rs1724343994

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Brain Malformations Variant Curation Expert Panel	RCV001836980	SCV001949971	likely pathogenic	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	2022-02-12	reviewed by expert panel	curation	The NM_006218.4:c.325_327del (p.Glu110del) variant is predicted to cause a change in the length of the PIK3CA protein due to an in-frame deletion of one amino acid. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; This variant has been shown to increase phosphorylation significantly above controls using patient derived cell lines (PMID: 29985963), it was identified in an individual with macrodactyly, in an individual with Cloves syndrome, two individuals with clinical diagnoses of MCAP and in two tumors within the COSMIC database (PMIDs: 28151489, 28502725, 29174369). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMIDs: 28502725, 28151489). In summary, this variant meets the criteria to be classified as Likely pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PS4, PS2_M; 7 points (VCEP specifications version 1; Approved: 1/31/2021)
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002254349	SCV002525577	pathogenic	not provided	2022-01-12	criteria provided, single submitter	clinical testing	This deletion of three nucleotides results in the in-frame loss of a single codon representing a glutamic acid at codon 110. Codon 110 is a highly conserved amino acid position located within a linker region adjacent to the regulatory p85/adaptor-binding domain of the PI3 kinase p110-alpha catalytic subunit (UniProt #P42336). This is a recurrent pathogenic variant. Several unrelated individuals with PIK3CA-related segmental overgrowth syndrome due to the PIK3CA p.Glu110del variant have previously been reported (PMID: 28151489 and others).
CeGaT Center for Human Genetics Tuebingen	RCV002254349	SCV002563799	uncertain significance	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447584	SCV004175378	likely pathogenic	CLOVES syndrome	2022-11-11	criteria provided, single submitter	clinical testing	The PIK3CA c.328_330del variant is classified as Likely Pathogenic (PS4, PM2, PM4) This PIK3CA c.328_330del variant results in an inframe deletion in exon 2/21. The variant has been reported in affected tissue in many patients with overgrowth syndrome (PMID:28151489, PMID:28502725, PMID:29174369) (PS4). This variant is absent from population databases (PM2). This variant is predicted to alter the length of the protein produced by this gene due to an Inframe deletion variant in a nonrepeat region (PM4). The variant has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 995382). It has not been reported in dbSNP or HGMD.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001289461	SCV004176922	pathogenic	PIK3CA related overgrowth syndrome	2023-09-29	criteria provided, single submitter	clinical testing	A PIK3CA c.328_330del (p.Glu110del) variant was identified at an allelic fraction consistent with somatic origin. The PIK3CA c.328_330del (p.Glu110del) variant has been reported in multiple individuals affected with PROS disorders (Chang F et al., PMID: 28502725; Siegel DH et al., PMID: 29174369; Steiner JE et al., PMID: 29516089; Parker VER et al., PMID: 30270358; Keppler-Noreuil KM et al., PMID: 31490637; McNulty SN et al., PMID: 31585106). This variant has been reported in the ClinVar database as a pathogenic somatic variant by two submitters and as a likely pathogenic germline variant by an expert panel (ClinVar Variation ID: 995382). It has also been reported in multiple cases in the cancer database COSMIC (Cosmic Genomic Mutation ID: COSV55874554). The PIK3CA c.328_330del (p.Glu110del) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the linker region, amino acids 106-186, between the adaptor-binding and Ras domains of p110a, which are defined as critical functional domains (Burke JE et al., PMID: 22949682). It is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region. Functional studies show this variant to be activating, as demonstrated by increased transformation ability in two different cell lines (Ng PK et al., PMID: 29533785). 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.328_330del (p.Glu110del) variant is classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001289461	SCV001474044	pathogenic	PIK3CA related overgrowth syndrome	2020-12-21	no assertion criteria provided	clinical testing
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527421	SCV005038934	likely pathogenic	Rare venous malformation	2024-03-19	no assertion criteria provided	clinical testing
Institute of Tissue Medicine and Pathology, University of Bern	RCV003447584	SCV005038935	likely pathogenic	CLOVES syndrome	2024-03-19	no assertion criteria provided	clinical testing
Institute of Tissue Medicine and Pathology, University of Bern	RCV004527420	SCV005038936	likely pathogenic	Angioosteohypertrophic syndrome	2024-03-19	no assertion criteria provided	clinical testing