Submissions for variant NM_006218.4(PIK3CA):c.344G>T (p.Arg115Leu)

dbSNP: rs200018596

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV002280087	SCV002568862	pathogenic	not provided		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096320	SCV003224758	uncertain significance	Cowden syndrome	2022-07-29	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg115 amino acid residue in PIK3CA. Other variant(s) that disrupt this residue have been observed in individuals with PIK3CA-related conditions (PMID: 23754335), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with macrodactyly (PMID: 23100325). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 115 of the PIK3CA protein (p.Arg115Leu).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458242	SCV004176939	likely pathogenic	PIK3CA related overgrowth syndrome	2023-10-18	criteria provided, single submitter	clinical testing	The PIK3CA c.344G>T (p.Arg115Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in twelve cases in the cancer database COSMIC (COSMIC ID: COSV55890007) and is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies show that the c.344G>T (p.Arg115Leu) variant confers a gain of function to the Pik3ca protein as demonstrated by increased cell growth, activation of the PI3K pathway (Lui VW et al., PMID: 23619167) and increased transformation ability in two different cell lines, as compared to wild-type Pik3ca (Ng PK et al., PMID: 29533785). Another variant in the same codon, (p.Arg115Pro), has been reported in an individual with macrodactyly and was considered pathogenic (Rios JJ et al., PMID: 23100325). 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 (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.344G>T (p.Arg115Leu) variant is classified as likely pathogenic.