ClinVar Miner

Submissions for variant NM_000535.5(PMS2):c.2264T>C (p.Ile755Thr) (rs386833410)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034625 SCV000043415 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
GeneDx RCV000034625 SCV000565421 uncertain significance not provided 2014-09-13 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2264T>C at the cDNA level, p.Ile755Thr (I755T) 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 pathogenic or benign. PMS2 Ile755Thr 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 Ile755Thr occurs at a position that is conserved across species and is located in the C-terminal nuclease domain (Fukui 2012). 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 Ile755Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000034625 SCV000697341 uncertain significance not provided 2016-01-25 criteria provided, single submitter clinical testing Variant summary: The c.2264T>C variant affects a conserved nucleotide, resulting in amino acid change from Ile to Thr. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may create multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant has been reported in one patient with colon cancer (Carneiro da Silva_2015), but not found in 114882 control chromosomes. Because of the insufficient evidence and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics RCV000708979 SCV000838168 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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