Submissions for variant NM_000535.7(PMS2):c.239T>G (p.Phe80Cys)

dbSNP: rs1064795697

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483447	SCV000571737	uncertain significance	not provided	2016-09-22	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.239T>G at the cDNA level, p.Phe80Cys (F80C) at the protein level, and results in the change of a Phenylalanine to a Cysteine (TTC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Phe80Cys 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 Phenylalanine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Phe80Cys occurs at a position that is conserved across species and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Phe80Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000797221	SCV000936770	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 80 of the PMS2 protein (p.Phe80Cys). 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: 422304). 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. 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.
Ambry Genetics	RCV002446938	SCV002732016	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-01	criteria provided, single submitter	clinical testing	The p.F80C variant (also known as c.239T>G), located in coding exon 3 of the PMS2 gene, results from a T to G substitution at nucleotide position 239. The phenylalanine at codon 80 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004003371	SCV004834870	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 80 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 not been identified 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.