ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.983A>G (p.Asp328Gly) (rs587782852)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132452 SCV000187546 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000656944 SCV000279136 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.983A>G at the cDNA level, p.Asp328Gly (D328G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant was observed in at least one individual with endometrial cancer and another with colorectal cancer whose tumor demonstrated loss of MLH1 and PMS2 expression on immunohistochemistry (Clendenning 2013, Ring 2016). PMS2 Asp328Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Asp328Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000226690 SCV000285167 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 328 of the PMS2 protein (p.Asp328Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. 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 been reported in an individual affected with endometrial cancer and in an individual with suspected Lynch syndrome (PMID: 27443514, 23017166). ClinVar contains an entry for this variant (Variation ID: 142960). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000411483 SCV000488354 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-03-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000214828 SCV000596478 uncertain significance not specified 2017-04-27 criteria provided, single submitter clinical testing
Color RCV000132452 SCV000686262 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing
Mendelics RCV000708988 SCV000838184 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000214828 SCV000918049 uncertain significance not specified 2017-09-19 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.983A>G (p.Asp328Gly) variant involves the alteration of a conserved nucleotide located in the Ribosomal protein S5 domain 2-type fold (via Interpro) and 2/3 in silico tools (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 5/245954 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, this observation needs to be cautiously considered due to the technology used inability to detect between the PMS2 gene and its pseudogene. Multiple publications have cited the variant in affected individuals diagnosed with CrC or endometrial cancer (Clendenning_2013, Ring_2016), with limited available information (ie, lack of co-occurrence and/or cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additonal information becomes available.

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