ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.901A>G (p.Lys301Glu) (rs757409701)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456989 SCV000551975 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-07 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 301 of the PMS2 protein (p.Lys301Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs757409701, ExAC 0.002%). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 411038). 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: "Possibly 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.
GeneDx RCV000766587 SCV000565391 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.901A>G at the cDNA level, p.Lys301Glu (K301E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Lys301Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Lys301Glu occurs at a position that is conserved across species and is located 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 evidence, it is unclear whether PMS2 Lys301Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483628 SCV000601863 uncertain significance not specified 2016-08-30 criteria provided, single submitter clinical testing

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