Submissions for variant NM_000314.8(PTEN):c.716T>C (p.Met239Thr)

dbSNP: rs786204871

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001026114	SCV001188433	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	The p.M239T variant (also known as c.716T>C), located in coding exon 7 of the PTEN gene, results from a T to C substitution at nucleotide position 716. The methionine at codon 239 is replaced by threonine, an amino acid with similar 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 a child with macrocephaly and mild intellectual disability as well as in his affected father, although the family's cancer history (if any) was not reported (Tatton-Brown K et al. Am. J. Hum. Genet., 2017 May;100:725-736). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001547857	SCV001767657	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); A published functional study demonstrates wildtype-like phosphatase activity (Mighell et al., 2018); This variant is associated with the following publications: (PMID: 28424201, 25669429, 32003824, 18626510, 28475857, 29706350)
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV002465824	SCV002760193	uncertain significance	PTEN hamartoma tumor syndrome	2022-10-14	criteria provided, single submitter	curation	Data included in classification: Segregation across 4 meiosis observed (PP1_mod) Present at <0.001% allele frequency in gnomAD (Observed in 1/125723 individuals in gnomAD v2.1.1) (PM2_sup) REVEL: 0.719 (PP3_sup) PTEN is constrained with a significance Z score (more than 3.09) (PP2_sup) Data not included in classification: Phenotypic features for the proband and their family members (none reach the minimum Cleveland Score threshold for application of PS4)
Invitae	RCV002465824	SCV003439550	uncertain significance	PTEN hamartoma tumor syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the PTEN protein (p.Met239Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 28475857, 32003824). ClinVar contains an entry for this variant (Variation ID: 826884). 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%. 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.