Submissions for variant NM_000535.7(PMS2):c.2168T>C (p.Leu723Pro)

dbSNP: rs1246922900

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526601	SCV000625590	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 723 of the PMS2 protein (p.Leu723Pro). 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: 455689). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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	RCV000566351	SCV000674234	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-28	criteria provided, single submitter	clinical testing	The p.L723P variant (also known as c.2168T>C), located in coding exon 12 of the PMS2 gene, results from a T to C substitution at nucleotide position 2168. The leucine at codon 723 is replaced by proline, an amino acid with similar 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.
Baylor Genetics	RCV003470718	SCV004205367	uncertain significance	Lynch syndrome 4	2023-10-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478115	SCV004218976	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000042 (1/238864 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000566351	SCV004359537	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 723 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 hereditary cancer 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.
GeneDx	RCV003478115	SCV005326001	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Fukui2011[Chapter])