Submissions for variant NM_000535.7(PMS2):c.1672A>G (p.Thr558Ala)

dbSNP: rs781106967

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478463	SCV000572597	uncertain significance	not provided	2017-01-02	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1672A>G at the cDNA level, p.Thr558Ala (T558A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in astrocytoma (Killela 2014). PMS2 Thr558Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Thr558Ala occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Thr558Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000773247	SCV000906863	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-18	criteria provided, single submitter	clinical testing
Invitae	RCV003758793	SCV004560839	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 558 of the PMS2 protein (p.Thr558Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422983). 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 PMS2 protein function. 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.