Submissions for variant NM_006218.4(PIK3CA):c.1528C>A (p.His510Asn)

gnomAD frequency: 0.00005  dbSNP: rs199747934

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547757	SCV000626807	uncertain significance	Cowden syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 510 of the PIK3CA protein (p.His510Asn). This variant is present in population databases (rs199747934, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with PIK3CA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456529). 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. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237894	SCV002009611	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004537902	SCV004177159	uncertain significance	PIK3CA-related disorder	2023-08-07	criteria provided, single submitter	clinical testing	The PIK3CA c.1528C>A (p.His510Asn) variant was identified at a near heterozygous allelic fraction. This variant has been reported in the ClinVar database as a variant of uncertain significance by two submitters (ClinVar Variation ID:456529), and it has been reported in one case in the cancer database COSMIC (COSMIC Mutation ID: COSV55977943). The PIK3CA c.1528C>A (p.His510Asn) variant is only observed on 8/152164 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are conflicting as to the impact of this variant on the PIK3CA function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.