ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.733C>A (p.Leu245Met) (rs201375580)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457456 SCV000552035 uncertain significance Hereditary nonpolyposis colon cancer 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 245 of the PMS2 protein (p.Leu245Met). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and methionine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; 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.
GeneDx RCV000034635 SCV000566385 uncertain significance not provided 2016-03-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.733C>A at the cDNA level, p.Leu245Met (L245M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). PMS2 Leu245Met 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 Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. PMS2 Leu245Met occurs at a position that is not conserved and is located within the ATPase 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 Leu245Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001026290 SCV001188639 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-12 criteria provided, single submitter clinical testing Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034635 SCV000043433 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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