ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2281G>C (p.Val761Leu) (rs201914670)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215841 SCV000278316 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000484575 SCV000566247 uncertain significance not specified 2017-04-19 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2281G>C at the cDNA level, p.Val761Leu (V761L) at the protein level, and results in the change of a Valine to a Leucine (GTC>CTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val761Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Val761Leu occurs at a position that is conserved among mammals and is located within the Nuclease domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Val761Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000553215 SCV000625608 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-04 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 761 of the PMS2 protein (p.Val761Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. The frequency data for this variant in the population databases (rs201914670, ExAC) 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 with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 233856). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.

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