ClinVar Miner

Submissions for variant NM_006218.4(PIK3CA):c.311C>T (p.Pro104Leu)

dbSNP: rs863225060
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001221647 SCV001393706 likely pathogenic Cowden syndrome 2023-11-10 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 104 of the PIK3CA protein (p.Pro104Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PIK3CA-related overgrowth syndrome (PMID: 27631024, 28151489). ClinVar contains an entry for this variant (Variation ID: 217291). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV002254285 SCV002525709 pathogenic not provided 2020-10-09 criteria provided, single submitter clinical testing The p.Pro104Leu variant has previously been reported as pathogenic in multiple unrelated individuals with PROS syndrome (PMID: 27631024, PMID: 28151489). Clinical details have included megalencephaly, hemimegalencephaly, and MCAP (megalencephaly-capillary malformation syndrome). Further supporting pathogenicity, the p.Pro104Leu as well as different missense variants at the same position (p.Pro104Arg, p.Pro104Thr) have been reported as oncogenic variants in multiple tumor types (COSMIC and cBioPortal Databases). This variant has not been observed in large population studies (Genome Aggregation Database v2.1.1).
Clinical Genomics Laboratory, Washington University in St. Louis RCV000201238 SCV000255981 likely pathogenic PIK3CA related overgrowth syndrome 2013-12-31 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004737318 SCV005364219 likely pathogenic PIK3CA-related disorder 2024-05-08 no assertion criteria provided clinical testing The PIK3CA c.311C>T variant is predicted to result in the amino acid substitution p.Pro104Leu. This variant was reported with de novo occurrence in two individuals with Megalencephaly-capillary malformation syndrome; one was mosaic the other apparently constitutional (Mirzaa et al 2016. PubMed ID: 27631024). This variant has not been reported in a large population database, indicating it is very rare. This variant is interpreted as likely pathogenic.

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