ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1999G>A (p.Glu667Lys) (rs587780045)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588762 SCV000149578 uncertain significance not provided 2016-11-23 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1999G>A at the cDNA level, p.Glu667Lys (E667K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu667Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Glu667Lys occurs at a position that is conserved across species and is located in the MLH1 interaction domain (Kondo 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Glu667Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115669 SCV000215560 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000468280 SCV000551985 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 667 of the PMS2 protein (p.Glu667Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs587780045, ExAC 0.01%). This variant has been reported in an individual affected with peritoneal cancer with a family history of breast cancer, female genital cancer, and bladder cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 127769). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Color RCV000115669 SCV000686173 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588762 SCV000697322 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1999G>A (p.Glu667Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 7/119840 control chromosomes at a frequency of 0.0000584, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant has been reported in multiple affected individuals without strong evidence for causality. However, the frequency in ExAC and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its many overlapping pseudogenes. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneKor MSA RCV000115669 SCV000822125 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588762 SCV000889617 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.