ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.787C>G (p.Leu263Val) (rs587779345)

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Total submissions: 5
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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 Hereditary nonpolyposis colorectal cancer type 4 2016-02-10 criteria provided, single submitter clinical testing
Invitae RCV000538871 SCV000625691 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 263 of the PMS2 protein (p.Leu263Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (rs587779345, ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (PMID: 27435373). ClinVar contains an entry for this variant (Variation ID: 91368). An experimental study has shown that this missense change retains sufficient DNA mismatch repair activity (PMID: 24027009). In summary, this variant is a rare missense change that does not have a significant impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000565209 SCV000663515 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000565209 SCV000909671 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing

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