ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.408G>A (p.Met136Ile) (rs1064794077)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484071 SCV000567744 uncertain significance not provided 2015-08-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.408G>A at the cDNA level, p.Met136Ile (M136I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Met136Ile 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 Isoleucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Met136Ile occurs at a position that is not conserved and is located in the ATPase domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether PMS2 Met136Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563701 SCV000670794 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000794842 SCV000934274 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 136 of the PMS2 protein (p.Met136Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. 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: 419740). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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