ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1233A>T (p.Glu411Asp) (rs587780040)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000679349 SCV000149561 uncertain significance not provided 2014-02-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1233A>T at the cDNA level, p.Glu411Asp (E411D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu411Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is a conservative amino acid substitution, altering a position that is conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider PMS2 Glu411Asp to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000115652 SCV000731346 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Glu411Asp variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but has been identified in 1/66182 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587780040). Computational prediction tools and conservation analysis suggest that the p.Glu411Asp variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical si gnificance of the p.Glu411Asp variant is uncertain.
Invitae RCV000629859 SCV000750815 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 411 of the PMS2 protein (p.Glu411Asp). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127755). 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.
PreventionGenetics,PreventionGenetics RCV000679349 SCV000806168 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing
Color RCV000771586 SCV000904175 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771586 SCV001170670 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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