Submissions for variant NM_000535.7(PMS2):c.206C>T (p.Ser69Leu)

dbSNP: rs730881914

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212838	SCV000211584	uncertain significance	not provided	2014-07-20	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.206C>T at the cDNA level, p.Ser69Leu (S69L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has been observed as a somatic variant in a pancreatic tumor (COSMIC), but has not been reported as a germline variant. PMS2 Ser69Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ser69Leu occurs at a position that is highly conserved across species and is located in the N-terminal ATPase domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Ser69Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160892	SCV000215489	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The p.S69L variant (also known as c.206C>T), located in coding exon 3 of the PMS2 gene, results from a C to T substitution at nucleotide position 206. The serine at codon 69 is replaced by leucine, an amino acid with 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516433	SCV003197750	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 69 of the PMS2 protein (p.Ser69Leu). 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: 182807). 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.