Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000115656 | SCV000149565 | uncertain significance | not specified | 2017-03-21 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.127G>A at the cDNA level, p.Val43Ile (V43I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA) in exon 2. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. PMS2 Val43Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we consider PMS2 Val43Ile to be a variant of unknown significance. The variant is found in HEREDICANCER panel(s). |
Ambry Genetics | RCV000213937 | SCV000274766 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-04 | criteria provided, single submitter | clinical testing | The p.V43I variant (also known as c.127G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 127. The valine at codon 43 is replaced by isoleucine, an amino acid with highly similar properties. 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, |
RCV000213937 | SCV000912098 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-02-04 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 43 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. |
Invitae | RCV001232239 | SCV001404787 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-05-24 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 43 of the PMS2 protein (p.Val43Ile). This variant is not present in population databases (gnomAD no frequency). 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: 127759). 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 not expected to disrupt PMS2 protein function. 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. |