ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1288A>G (p.Thr430Ala) (rs587781382)

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 RCV000129211 SCV000183961 likely benign Hereditary cancer-predisposing syndrome 2019-03-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000232320 SCV000285060 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 430 of the PMS2 protein (p.Thr430Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 140937). 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 alanine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000486562 SCV000566494 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1288A>G at the cDNA level, p.Thr430Ala (T430A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Thr430Ala was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Thr430Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129211 SCV001353134 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-18 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.