ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2033T>C (p.Ile678Thr) (rs587782553)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131767 SCV000186813 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000196874 SCV000255288 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 678 of the PMS2 protein (p.Ile678Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. The frequency data for this variant in the population databases (rs587782553, 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: 142569). 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: "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.
GeneDx RCV000217701 SCV000279464 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2033T>C at the cDNA level, p.Ile678Thr (I678T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. PMS2 Ile678Thr 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 Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ile678Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated 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 evidence, it is unclear whether PMS2 Ile678Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000217701 SCV001361928 uncertain significance not specified 2019-07-15 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2033T>C (p.Ile678Thr) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 196332 control chromosomes, however the technology utilized for this dataset does not rule out pseudogene interference and thus cannot be relied upon to make any conclusions about variant significance for this gene. To our knowledge, no occurrence of c.2033T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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