ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2036T>C (p.Ile679Thr) (rs778251286)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220917 SCV000273385 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000229051 SCV000285099 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-01-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 679 of the PMS2 protein (p.Ile679Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. 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 individuals affected with Lynch syndrome or suspected Lynch syndrome (PMID: 28874130, 26437257). ClinVar contains an entry for this variant (Variation ID: 229989). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000589548 SCV000566456 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2036T>C at the cDNA level, p.Ile679Thr (I679T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ile679Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ile679Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Ile679Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589548 SCV000697325 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2036T>C (p.Ile679Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 1/44144 control chromosomes at a frequency of 0.0000227, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in one patient with suspected LS, however without strong evidence for pathogenicity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000662646 SCV000785333 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 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.