ClinVar

Description

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. This variant disrupts the C-tail domain and PDZ binding domain of the PTEN protein (PMID: 25448482, 25336918, 24905788) and several critical phosphorylation sites within the C-tail domain, which are important for regulating PTEN protein stability and function (PMID: 12297295, 10866658, 11035045, 10468583). While functional studies have not been performed to directly test the effect of this variant on PTEN protein function, this suggests that disruption of this region of the protein is causative of disease. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. 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. ClinVar contains an entry for this variant (Variation ID: 566673). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 310 of the PTEN protein (p.Asp310Gly). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein.