Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000471564 | SCV000552011 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 613 of the PMS2 protein (p.Lys613Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 411056). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |
| Ambry Genetics | RCV000564365 | SCV000670811 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-30 | criteria provided, single submitter | clinical testing | The p.K613Q variant (also known as c.1837A>C), located in coding exon 11 of the PMS2 gene, results from an A to C substitution at nucleotide position 1837. The lysine at codon 613 is replaced by glutamine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000564365 | SCV001358467 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-04-07 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamine at codon 613 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31404 chromosomes 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001553758 | SCV001774752 | uncertain significance | not specified | 2021-07-13 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.1837A>C (p.Lys613Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1837A>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |