Submissions for variant NM_000535.7(PMS2):c.1753C>A (p.Leu585Ile)

gnomAD frequency: 0.00001  dbSNP: rs63750947

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216706	SCV000278562	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-03	criteria provided, single submitter	clinical testing	The p.L585I variant (also known as c.1753C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1753. The leucine at codon 585 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been identified in cis with a pathogenic PMS2 mutation in multiple Dutch individuals with HNPCC/Lynch syndrome, including several whose tumors were MSI-H or demonstrated loss of PMS2 expression by IHC (Hendriks YM et al. Gastroenterology 2006 Feb; 130(2):312-22; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179). This variant was shown to be mismatch-repair proficient in vitro (Drost M et al. Hum Mutat, 2013 Nov;34:1477-80). This amino acid position is poorly 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.
GeneDx	RCV001529737	SCV000518107	likely benign	not provided	2019-05-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24027009, 27435373, 16472587, 22290698, 26333163, 28135145)
Invitae	RCV000524448	SCV000552041	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 585 of the PMS2 protein (p.Leu585Ile). This variant is present in population databases (rs63750947, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 16472587, 27435373, 28135145, 34326862). ClinVar contains an entry for this variant (Variation ID: 91313). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 24027009). 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	RCV000216706	SCV000911785	likely benign	Hereditary cancer-predisposing syndrome	2020-11-03	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001529737	SCV002009108	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001529737	SCV004218965	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/129142 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 16472587 (2006), 27435373 (2016), 28135145 (2017)) and endometrial cancer (PMID: 27435373 (2016)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). An invitro based functional study has reported that this variant does not have a deleterious effect on PMS2 mismatch repair activity (PMID: 24027009 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000216706	SCV004228057	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000216706	SCV000788109	likely benign	Hereditary cancer-predisposing syndrome	2017-07-31	no assertion criteria provided	clinical testing