Submissions for variant NM_000535.7(PMS2):c.401G>A (p.Arg134Gln)

dbSNP: rs771300829

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482875	SCV000572919	uncertain significance	not provided	2017-02-03	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.401G>A at the cDNA level, p.Arg134Gln (R134Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Arg134Gln 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 Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Arg134Gln occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the ATPase domain (Guarne 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Arg134Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000630071	SCV000751027	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 134 of the PMS2 protein (p.Arg134Gln). This variant is present in population databases (rs771300829, gnomAD 0.02%). 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: 423246). 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 PMS2 protein function with a positive 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.
Color Diagnostics, LLC DBA Color Health	RCV001192083	SCV001360037	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 134 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 6/251142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001192083	SCV002619653	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-11	criteria provided, single submitter	clinical testing	The p.R134Q variant (also known as c.401G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 401. The arginine at codon 134 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected as homozygous in an individual with no reported features of CMMRD-associated disease (Ambry internal data). This amino acid position is well 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.