ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.149G>A (p.Gly50Asp) (rs539285592)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586511 SCV000211582 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.149G>A at the cDNA level, p.Gly50Asp (G50D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gly50Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Gly50Asp occurs at a position that is conserved across species and is in the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Gly50Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000542157 SCV000625530 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-05-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 50 of the PMS2 protein (p.Gly50Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs539285592, ExAC 0.009%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 182805). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C65"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000571665 SCV000670761 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-13 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000571665 SCV000686130 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586511 SCV000697298 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.149G>A (p.Gly50Asp) variant located in the Histidine kinase-like ATPase, C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/115490 (1/57745), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMS2 variant of 1/8802. In addition, one clinical diagnostic laboratories has classified this variant as "uncertain significance." The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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