Submissions for variant NM_000535.7(PMS2):c.2392T>C (p.Cys798Arg)

dbSNP: rs1554293839

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000662657	SCV000785344	uncertain significance	Lynch syndrome 4	2017-07-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800315	SCV000940022	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 798 of the PMS2 protein (p.Cys798Arg). 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: 548764). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV002458176	SCV002737116	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-13	criteria provided, single submitter	clinical testing	The p.C798R variant (also known as c.2392T>C), located in coding exon 14 of the PMS2 gene, results from a T to C substitution at nucleotide position 2392. The cysteine at codon 798 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was identified in 1/136 Turkish colorectal cancer patients undergoing multigene panel testing for hereditary cancer risk (Erdem HB et al. Turk J Med Sci, 2020 06;50:1015-1021). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Myriad Genetics, Inc.	RCV000662657	SCV004019744	uncertain significance	Lynch syndrome 4	2023-04-03	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.