Submissions for variant NM_006218.4(PIK3CA):c.1133G>A (p.Cys378Tyr)

dbSNP: rs397514565

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000806643	SCV000946653	pathogenic	Cowden syndrome	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 39704). This missense change has been observed in individual(s) with megalencephaly-capillary malformation syndrome (MCAP) and symptoms consistent with PIK3CA-related overgrowth syndrome (PMID: 22729224, 27631024, 28151489). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 378 of the PIK3CA protein (p.Cys378Tyr).
Centogene AG - the Rare Disease Company	RCV000032908	SCV002059600	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2018-12-20	criteria provided, single submitter	clinical testing
3billion	RCV000032908	SCV003842078	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. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 26637981). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039704). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27631024). A different missense change at the same codon (p.Cys378Arg) has been reported to be associated with PIK3CA related disorder (ClinVar ID: VCV000917489). The variant was detected at ~13% allele frequency, suggesting mosaic state. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Care4Rare-SOLVE, CHEO	RCV000201233	SCV003932121	pathogenic	PIK3CA related overgrowth syndrome		criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003398587	SCV004118723	pathogenic	PIK3CA-related condition	2022-08-30	criteria provided, single submitter	clinical testing	The PIK3CA c.1133G>A variant is predicted to result in the amino acid substitution p.Cys378Tyr. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic.
OMIM	RCV000032908	SCV000056680	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2012-06-24	no assertion criteria provided	literature only
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000201233	SCV000255988	pathogenic	PIK3CA related overgrowth syndrome	2014-12-08	no assertion criteria provided	clinical testing