Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000612857 | SCV000731408 | uncertain significance | not specified | 2017-02-20 | criteria provided, single submitter | clinical testing | The p.Lys670Glu variant in PMS2 has not been previously reported in individuals with Lynch syndrome or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Lys670Glu variant may impact the protein, though this information is not predictive enough to determine pathogen icity. In summary, the clinical significance of the p.Lys670Glu variant is uncer tain. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000612857 | SCV001363170 | uncertain significance | not specified | 2019-04-22 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.2008A>G (p.Lys670Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 165648 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2008A>G, has been reported in the literature in individuals affected with breast cancer (Li_2018). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Labcorp Genetics |
RCV001214793 | SCV001386497 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-09-11 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 670 of the PMS2 protein (p.Lys670Glu). 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 missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer (PMID: 29752822, 35449176). ClinVar contains an entry for this variant (Variation ID: 517233). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 | RCV002420652 | SCV002724277 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-29 | criteria provided, single submitter | clinical testing | The p.K670E variant (also known as c.2008A>G), located in coding exon 12 of the PMS2 gene, results from an A to G substitution at nucleotide position 2008. The lysine at codon 670 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). This variant was also identified in 2/937 Chinese breast cancer patients undergoing multigene panel testing (Li JY et al. Int J Cancer, 2019 01;144:281-289). This amino acid position is highly 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. |
| Fulgent Genetics, |
RCV002483696 | SCV002792731 | uncertain significance | Lynch syndrome 4; Mismatch repair cancer syndrome 4 | 2021-10-21 | criteria provided, single submitter | clinical testing |