Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000131767 | SCV000186813 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-31 | criteria provided, single submitter | clinical testing | The p.I678T variant (also known as c.2033T>C), located in coding exon 12 of the PMS2 gene, results from a T to C substitution at nucleotide position 2033. The isoleucine at codon 678 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000196874 | SCV000255288 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-16 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 678 of the PMS2 protein (p.Ile678Thr). The frequency data for this variant in the population databases (gnomAD) 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 affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142569). 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 expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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 |
RCV000217701 | SCV000279464 | uncertain significance | not specified | 2017-03-20 | criteria provided, single submitter | clinical testing | This variant is denoted PMS2 c.2033T>C at the cDNA level, p.Ile678Thr (I678T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. PMS2 Ile678Thr 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 Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ile678Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in 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 evidence, it is unclear whether PMS2 Ile678Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000217701 | SCV001361928 | uncertain significance | not specified | 2019-07-15 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.2033T>C (p.Ile678Thr) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 196332 control chromosomes, however the technology utilized for this dataset does not rule out pseudogene interference and thus cannot be relied upon to make any conclusions about variant significance for this gene. To our knowledge, no occurrence of c.2033T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Baylor Genetics | RCV003462022 | SCV004207834 | uncertain significance | Lynch syndrome 4 | 2023-05-21 | criteria provided, single submitter | clinical testing |