Submissions for variant NM_000314.8(PTEN):c.277C>T (p.His93Tyr)

dbSNP: rs786204927

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801387	SCV000941161	pathogenic	PTEN hamartoma tumor syndrome	2024-06-26	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 93 of the PTEN protein (p.His93Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 9685848, 24778394; Invitae). ClinVar contains an entry for this variant (Variation ID: 646993). 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 expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302, 21828076). This variant disrupts the p.His93 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15805158, 20718038, 21828076, 22505997, 24345843, 25647146, 26579216). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002440676	SCV002748229	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-27	criteria provided, single submitter	clinical testing	The p.H93Y variant (also known as c.277C>T), located in coding exon 5 of the PTEN gene, results from a C to T substitution at nucleotide position 277. The histidine at codon 93 is replaced by tyrosine, an amino acid with similar properties. This variant has been detected in multiple individuals with Cowden syndrome/PTEN-related disorder (Kohno T et al. Jpn. J. Cancer Res., 1998 May;89:471-4; Ngeow J et al. J. Clin. Oncol., 2014 Jun;32:1818-24; Frazier TW et al. Mol. Psychiatry, 2015 Sep;20:1132-8; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). In addition, two independent functional studies demonstrated greater than 50% reduction in phosphatase activity for this variant (Han SY et al. Cancer Res., 2000 Jun;60:3147-51; Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). 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.	RCV003453667	SCV004188728	likely pathogenic	Cowden syndrome 1	2023-09-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9685848, 24778394].