Submissions for variant NM_000535.7(PMS2):c.787C>G (p.Leu263Val)

dbSNP: rs587779345

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160886	SCV000211575	uncertain significance	not provided	2016-11-23	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.787C>G at the cDNA level, p.Leu263Val (L263V) at the protein level, and results in the change of a Leucine to a Valine (CTG>GTG). Functional analysis by a modified cell-free assay demonstrated repair efficiency significantly higher than a known repair deficient control (p<0.05) (Drost 2103). PMS2 Leu263Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. PMS2 Leu263Val occurs at a position that is not conserved and is located in the ATPase domain (Guarne 2001). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Leu263Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000410252	SCV000488270	uncertain significance	Lynch syndrome 4	2016-02-10	criteria provided, single submitter	clinical testing
Invitae	RCV000538871	SCV000625691	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	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 263 of the PMS2 protein (p.Leu263Val). This variant is present in population databases (rs587779345, gnomAD 0.0009%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 27435373). ClinVar contains an entry for this variant (Variation ID: 91368). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000565209	SCV000663515	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	The p.L263V variant (also known as c.787C>G), located in coding exon 7 of the PMS2 gene, results from a C to G substitution at nucleotide position 787. The leucine at codon 263 is replaced by valine, an amino acid with highly similar properties. This variant has been reporting in an individual suspected of having Lynch syndrome or CMMRD; however, a functional assay showed intact DNA mismatch repair activity (Drost M et al. Hum. Mutat. 2013 Nov;34:1477-80; van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). This amino acid position is not well 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.
Color Diagnostics, LLC DBA Color Health	RCV000565209	SCV000909671	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 263 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study have shown that this variant has no impact on mismatch repair activity in vitro (PMID: 24027009). This variant has been observed in a cohort of individuals with a personal or family history of Lynch syndrome-associated disease (PMID: 27435373). This variant has been identified in 1/250566 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267844	SCV002550737	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410252	SCV004019977	uncertain significance	Lynch syndrome 4	2023-04-05	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.
Baylor Genetics	RCV000410252	SCV004207829	uncertain significance	Lynch syndrome 4	2023-05-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160886	SCV004563446	uncertain significance	not provided	2022-12-20	criteria provided, single submitter	clinical testing	The PMS2 c.787C>G; p.Leu263Val variant (rs587779345) is reported in the literature in an individual with suspected Lynch syndrome (van der Klift 2016). Functional analyses found that this variant protein is MMR proficient (Drost 2013). This variant is also reported in ClinVar (Variation ID: 91368) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 263 is weakly conserved, but computational analyses predict that this variant is neutral (REVEL: 0.422). Due to limited information, the clinical significance of the p.Leu263Val variant is uncertain at this time. References: Drost M et al. Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene. Hum Mutat. 2013 Nov;34(11):1477-80. PMID: 24027009. van der Klift HM et al. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. Hum Mutat. 2016 Nov;37(11):1162-1179. PMID: 27435373.