Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000168042 | SCV000218695 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2019-11-30 | criteria provided, single submitter | clinical testing | This sequence change replaces valine with isoleucine at codon 607 of the PMS2 protein (p.Val607Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 188154). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. |
| Gene |
RCV000482215 | SCV000572229 | uncertain significance | not provided | 2018-04-19 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.1819G>A at the cDNA level, p.Val607Ile (V607I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Val607Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000562276 | SCV000670742 | likely benign | Hereditary cancer-predisposing syndrome | 2019-01-22 | criteria provided, single submitter | clinical testing | Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign) |
| Color | RCV000562276 | SCV000912092 | likely benign | Hereditary cancer-predisposing syndrome | 2017-03-21 | criteria provided, single submitter | clinical testing |