Submissions for variant NM_000535.7(PMS2):c.2338C>A (p.Pro780Thr)

gnomAD frequency: 0.00003  dbSNP: rs1064796041

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480063	SCV000572423	uncertain significance	not provided	2019-01-03	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2338C>A at the cDNA level, p.Pro780Thr (P780T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Pro780Thr is located in the endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Pro780Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573429	SCV000670833	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-22	criteria provided, single submitter	clinical testing	The p.P780T variant (also known as c.2338C>A), located in coding exon 14 of the PMS2 gene, results from a C to A substitution at nucleotide position 2338. The proline at codon 780 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000630117	SCV000751073	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 780 of the PMS2 protein (p.Pro780Thr). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. 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: 422851). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Color Diagnostics, LLC DBA Color Health	RCV000573429	SCV004359011	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 780 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/30860 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.