ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2335G>A (p.Gly779Arg) (rs587780053)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212870 SCV000149591 uncertain significance not provided 2015-04-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2335G>A at the cDNA level, p.Gly779Arg (G779R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gly779Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Gly779Arg occurs at a position that is well conserved across species and is located within the nuclease domain (Fukui 2011). 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 Gly779Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115682 SCV000186986 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000227932 SCV000285116 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 779 of the PMS2 protein (p.Gly779Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. 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: 127778). 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 C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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