Submissions for variant NM_000314.8(PTEN):c.959T>C (p.Leu320Ser)

dbSNP: rs1114167667

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001347116	SCV001541361	uncertain significance	PTEN hamartoma tumor syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 320 of the PTEN protein (p.Leu320Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 31149344). ClinVar contains an entry for this variant (Variation ID: 1043063). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PTEN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 28263967, 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.
GeneDx	RCV001586139	SCV001820464	pathogenic	not provided	2021-02-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced protein expression, increased AKT expression, abnormal cellular localization (Yang et al., 2017); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28263967, 31454965, 25669429, 31149344, 27741505)
Ambry Genetics	RCV002377474	SCV002690620	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-04	criteria provided, single submitter	clinical testing	The p.L320S variant (also known as c.959T>C), located in coding exon 8 of the PTEN gene, results from a T to C substitution at nucleotide position 959. The leucine at codon 320 is replaced by serine, an amino acid with dissimilar properties. This variant has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur J Hum Genet, 2015 Nov;23:1538-43). This variant was also reported in an child with developmental delay, macrocephaly, autism, and hypotonia (Ueno Y et al. Hum Genome Var, 2019 May;6:25). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955) while phosphatase activity was similar to wildtype in an in vitro assay, which would, however, be unable to identify localization defects and reduced protein stability (Yang JM et al. Oncogene, 2017 06;36:3673-3685). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003449975	SCV004189536	likely pathogenic	Cowden syndrome 1	2023-10-03	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 28263967, 29785012].