ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1041G>C (p.Glu347Asp) (rs150515238)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115648 SCV000149557 uncertain significance not provided 2014-03-05 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1041G>C at the cDNA level, p.Glu347Asp (E347D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu347Asp 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 Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution and is unlikely to affect protein integrity. PMS2 Glu347Asp occurs at a position that is well conserved across species and is located in 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 Glu347Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000411537 SCV000487856 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2015-11-23 criteria provided, single submitter clinical testing
Invitae RCV000458229 SCV000552038 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 347 of the PMS2 protein (p.Glu347Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs150515238, ExAC 0.06%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127752). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000565848 SCV000670863 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-08 criteria provided, single submitter clinical testing Insufficient evidence;In silico models in agreement (benign)
Color RCV000565848 SCV001353141 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-15 criteria provided, single submitter clinical testing

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