Submissions for variant NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys)

dbSNP: rs867262025

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Brain Malformations Variant Curation Expert Panel	RCV001836817	SCV001949966	pathogenic	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	2022-02-12	reviewed by expert panel	curation	The c.2176G>A (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Glu726Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PIK3CA, in which the variant was identified, 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 (PP2). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in at least 15 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 28566443), and is in at least 15 tumor samples in the literature and COSMIC (PMID: 22729224, PMID: 28941273, PMID: 24497998 )). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMIDs: 22729224, 22729224). In summary, this variant meets the criteria to be classified as 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, PP2, PS4_VS, PS2; 14 points (VCEP specifications version 1; Approved: 1/31/2021)
GeneDx	RCV000484330	SCV000568812	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	Not observed 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: 34093841, 35238469, 31699932, 24497998, 22729224, 26351730, 28941273, 33644862)
Ambry Genetics	RCV000624735	SCV000742002	pathogenic	Inborn genetic diseases	2024-02-20	criteria provided, single submitter	clinical testing	The c.2176G>A (p.E726K) alteration is located in exon 14 (coding exon 13) of the PIK3CA gene. This alteration results from a G to A substitution at nucleotide position 2176, causing the glutamic acid (E) at amino acid position 726 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo post-zygotic mutation in multiple individual with features consistent with PIK3CA-related disorders (Rivière, 2012; Tapper, 2014; McDermott, 2016; Mirzaa, 2016; Kuentz, 2017; McDermott, 2017; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). A functional analysis of patient derived cells have shown a significant increase of phosphorylation levels for p.E726K (Leiter, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000484330	SCV001248955	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV001851018	SCV002246067	pathogenic	Cowden syndrome	2023-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 726 of the PIK3CA protein (p.Glu726Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome and/or PIK3CA-related conditions (PMID: 22729224, 24497998, 26351730, 27631024; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376476). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. For these reasons, this variant has been classified as Pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000484330	SCV002525569	pathogenic	not provided	2019-10-24	criteria provided, single submitter	clinical testing	This variant results in a lysine residue replacing a glutamic acid residue at position 726 within the PIK3CA protein. This variant has been previously reported in several unrelated individuals with PIK3CA related overgrowth syndrome (PMID:22729224, PMID:27631024).
3billion	RCV003152707	SCV003841611	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000376476). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22729224). Different missense changes at the same codon (p.Glu726Ala, p.Glu726Gly) have been reported to be associated with PIK3CA-related disorder (ClinVar ID: VCV000376477 / PMID: 29549527). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV003152707	SCV003919026	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2023-04-20	criteria provided, single submitter	research
Care4Rare-SOLVE, CHEO	RCV003233633	SCV003932122	pathogenic	PIK3CA related overgrowth syndrome		criteria provided, single submitter	research
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003233633	SCV004176916	pathogenic	PIK3CA related overgrowth syndrome	2023-09-15	criteria provided, single submitter	clinical testing	The PIK3CA c.2176G>A (p.Glu726Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in several individuals affected with PIK3CA-Related Overgrowth Spectrum (PROS) disorders (Kuentz P et al., PMID: 28151489; Gökpınar İli E et al., PMID: 35238469; Mirzaa G et al., PMID: 27631024; McNulty SN et al., PMID: 31585106; Leiter SM et al., PMID: 2856644) and in multiple cases in the cancer database COSMIC (Genomic Mutation ID COSV55875460). It has also been classified in the ClinVar database as a germline pathogenic variant by four submitters and as a somatic pathogenic variant by three submitters (ClinVar ID: 376476). The PIK3CA c.2176G>A (p.Glu726Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies using patient-derived cells studies show that this glutamic acid substitution to lysine at codon 726 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling, indicating that this variant impacts protein function (Leiter SM et al., PMID: 2856644). The PIK3CA gene is defined by the ClinGen Brain Malformations Variant Curation 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 (Lai A et al., PMID: 35997716). 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.2176G>A (p.Glu726Lys) variant is classified as pathogenic.
Database of Curated Mutations (DoCM)	RCV000437047	SCV000506905	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419986	SCV000506906	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429813	SCV000506907	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440466	SCV000506908	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424090	SCV000506909	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431306	SCV000506910	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441124	SCV000506911	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423869	SCV000506912	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only