ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.784G>A (p.Ala262Thr) (rs779625900)

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 RCV000167024 SCV000217847 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000481531 SCV000567964 uncertain significance not provided 2016-07-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.784G>A at the cDNA level, p.Ala262Thr (A262T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ala262Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ala262Thr occurs at a position that is not conserved and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Ala262Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000707037 SCV000836115 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 262 of the PMS2 protein (p.Ala262Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs779625900, ExAC 0.002%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 187306). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV000167024 SCV000904184 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-16 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.