ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.858C>A (p.Asp286Glu) (rs201921616)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566790 SCV000670786 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034636 SCV000043432 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000566790 SCV000911241 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000034636 SCV000572314 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.858C>A at the cDNA level, p.Asp286Glu (D286E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAA). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). PMS2 Asp286Glu 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 Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. PMS2 Asp286Glu occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Asp286Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000034636 SCV000697394 uncertain significance not provided 2016-01-11 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of an Aspartate (D) with a Glutamic acid (E). Both residues are medium size and acidic, therefore this Aspartate to Glutamic acid substitution likely does not alter the physico-chemical properties of the protein. It is absent from the large and broad cohorts of the ExAC project and to our knowledge, it was not reported in Lynch syndrome spectrum patients either. In vitro/vivo studies to reporting the impact on the function of the protein were not published at the time of scoring. Due to the lack of clinical and functional data, the variant was classified as a variant of uncertain significance until more information becomes available.
Invitae RCV000529412 SCV000625702 uncertain significance Hereditary nonpolyposis colon cancer 2017-07-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 286 of the PMS2 protein (p.Asp286Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic 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: 41720). 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 glutamic 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.

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