ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.922G>A (p.Glu308Lys) (rs587781358)

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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 RCV000129150 SCV000183873 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-24 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000590123 SCV000566372 uncertain significance not provided 2015-04-28 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.922G>A at the cDNA level, p.Glu308Lys (E308K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu308Lys 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 Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Glu308Lys occurs at a position that is 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 Glu308Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590123 SCV000697400 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The c.922G>A (p.Glu308Lys) in PMS2 gene is a missense change that involves a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant of interest is absent from the control population dataset of ExAC and has not, to our knowledge, been reported in affected individuals via published reports. c.922G>A is listed as VUS by a reputable database/clinical laboratory without evidence to independently evaluate. Taking together, the variant was classified as VUS.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000480731 SCV000731349 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Glu308Lys variant in PMS2 has not been previously reported in individuals with colorectal cancer and was absent from large population studies. Computation al prediction tools and conservation analysis suggest that the p.Glu308Lys varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. In summary, the clinical significance of the p.Glu308Lys variant is uncertain.
Invitae RCV000629843 SCV000750799 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 308 of the PMS2 protein (p.Glu308Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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: 140902). 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 disruptive, 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.
Color RCV000129150 SCV001353840 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing

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