ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.675A>C (p.Glu225Asp) (rs876661233)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217891 SCV000279856 uncertain significance not provided 2016-02-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.675A>C at the cDNA level, p.Glu225Asp (E225D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu225Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. PMS2 Glu225Asp occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the ATPase domain (Guarne 2001, 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 Glu225Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563797 SCV000664903 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000698159 SCV000826803 uncertain significance Hereditary nonpolyposis colon cancer 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 225 of the PMS2 protein (p.Glu225Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. 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: 234813). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Fulgent Genetics,Fulgent Genetics RCV000765964 SCV000897385 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing

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