ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2390T>C (p.Met797Thr) (rs267608152)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486445 SCV000566179 uncertain significance not provided 2015-04-09 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2390T>C at the cDNA level, p.Met797Thr (M797T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Met797Thr 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 Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Met797Thr occurs at a position that is conserved across species and is located in the Nuclease domain (Fukui 2011). 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 Met797Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000706385 SCV000835430 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 797 of the PMS2 protein (p.Met797Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine 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 not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 418826). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly 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.
Ambry Genetics RCV001015376 SCV001176201 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing Insufficient evidence

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