PTEN NM_000314.8:c.571G>T, Val191Leu

The p.V191L variant (also known as c.571G>T), located in coding exon 6 of the PTEN gene, results from a G to T substitution at nucleotide position 571. The valine at codon 191 is replaced by leucine, an amino acid with highly similar properties. This variant demonstrated wildtype-like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 191 of the PTEN protein (p.Val191Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 404173). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 29785012). 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.