ClinVar

Description

The c.737C>T (p.P246L) alteration is located in exon 7 (coding exon 7) of the PTEN gene. This alteration results from a C to T substitution at nucleotide position 737, causing the proline (P) at amino acid position 246 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported as heterozygous in multiple individuals who met clinical criteria for PTEN hamartoma tumor syndrome, and was determined to be the result of a de novo mutation in one individual (Hobert, 2012; Vanderver, 2014; Shao, 2020). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). A yeast-based assay demonstrated that this alteration combined with another missense alteration failed to rescue yeast cells from p110alpha CAAX induced growth inhibition and release GFP-AKt1 from the cellular membrane, although both alterations by themselves had similar activity to wildtype. The authors postulated that this assay suggests patient-dependent loss of function effects (Andrés-Pons, 2007). In addition, p.P246L has been described as a pathogenic mutation leading to impaired PTEN protein levels and signaling in Lhermitte-Dulcose disease cells (Zhou, 2003). In another functional assay, this variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.