ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2068A>C (p.Lys690Gln) (rs587781909)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130250 SCV000185094 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000222360 SCV000279603 uncertain significance not provided 2018-11-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2068A>C at the cDNA level, p.Lys690Gln (K690Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAA>CAA). PMS2 Lys690Gln has been reported in at least one individual with breast cancer and another with endometrial cancer (Tung 2015, Ring 2016). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Lys690Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000230692 SCV000285100 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 690 of the PMS2 protein (p.Lys690Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 141651). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV001251272 SCV001426798 uncertain significance not specified 2020-07-16 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2068A>C (p.Lys690Gln) results in a conservative amino acid change located in the C-terminal dimerization domain (IPR014790) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 216714 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (4.6e-05 vs 0.00011), allowing no conclusion about variant significance. In addition, the variant is located in a region that is highly homologous to PMS2 pseudogenes and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. The variant, c.2068A>C, has been reported in the literature an individual affected with breast cancer and in another individual with endometrial carcinoma (Tung_2015, Ring_2016), however it was also found in two individuals in a non-cancer related cohort (Kraemer_2019). These reports do 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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.