ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2240G>C (p.Arg747Thr) (rs587782671)

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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 RCV000132094 SCV000187158 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524462 SCV000255290 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 747 of the PMS2 protein (p.Arg747Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. The frequency data for this variant in the population databases (rs587782671, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been reported in an individual with colon polyps (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 142721). 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 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000195874 SCV000266220 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000195874 SCV000469716 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781753 SCV000920048 uncertain significance not specified 2018-05-16 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2240G>C (p.Arg747Thr) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 116836 control chromosomes in the ExAC database, including 1 homozygotes. However, this data should be used with caution as the sequencing technology utalized cannot rule out pseudogene interference. c.2240G>C has been reported in the literature in a patient with polyps, however without ruling out pseudogene intereference and lacking co-segregation data (Shirts_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985905 SCV001134590 uncertain significance not provided 2018-11-24 criteria provided, single submitter clinical testing

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