Submissions for variant NM_000535.7(PMS2):c.2012C>G (p.Thr671Arg)

dbSNP: rs587780046

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214621	SCV000279993	uncertain significance	not provided	2016-03-13	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2012C>G at the cDNA level, p.Thr671Arg (T671R) at the protein level, and results in the change of a Threonine to an Arginine (ACG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Thr671Arg 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 Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Thr671Arg occurs at a position that is not conserved and is located in the Nuclease domain (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 Thr671Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001211374	SCV001382911	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-02-15	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234906). The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change replaces threonine with arginine at codon 671 of the PMS2 protein (p.Thr671Arg). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and arginine.