ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.139C>G (p.Leu47Val) (rs766203500)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205693 SCV000259856 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 47 of the PMS2 protein (p.Leu47Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs766203500, ExAC 0.06%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 219785). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect 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 RCV000575149 SCV000663454 likely benign Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl RCV000662464 SCV000784946 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-02-14 criteria provided, single submitter clinical testing
Color RCV000575149 SCV000910994 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193970 SCV001363167 uncertain significance not specified 2019-01-18 criteria provided, single submitter clinical testing Variant summary: The variant, PMS2 c.139C>G (p.Leu47Val) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain and Histidine kinase/HSP90-like ATPase domain of the encoded protein sequence. Several in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 240416 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.139C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (uncertain significance (2) and Likely benign (1)). Based on the evidence outlined above, the variant was classified as uncertain significance.

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