Submissions for variant NM_000535.7(PMS2):c.403C>G (p.Leu135Val)

gnomAD frequency: 0.00001  dbSNP: rs876658423

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219595	SCV000273611	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.L135V variant (also known as c.403C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide position 403. The leucine at codon 135 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000472073	SCV000551974	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 135 of the PMS2 protein (p.Leu135Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 230165). 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.
Color Diagnostics, LLC DBA Color Health	RCV000219595	SCV000691073	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 135 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 PMS2-related disorders in the literature. This variant has been identified in 1/251142 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985910	SCV001134601	uncertain significance	not provided	2018-12-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001293981	SCV001482721	uncertain significance	Lynch syndrome 4	2018-12-18	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000985910	SCV004163710	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PMS2: PM2:Supporting, BP4
PreventionGenetics, part of Exact Sciences	RCV003982963	SCV004797204	uncertain significance	PMS2-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The PMS2 c.403C>G variant is predicted to result in the amino acid substitution p.Leu135Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/230165/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987454	SCV004803941	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.403C>G (p.Leu135Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.403C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 230165). Based on the evidence outlined above, the variant was classified as uncertain significance.