ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1720C>T (p.Pro574Ser) (rs758018736)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566855 SCV000663444 likely benign Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588325 SCV000697310 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The c.1720C>T (p.Pro574Ser) in PMS2 gene is a missense change that alters a non-conserved nucleotide and 5/5 in silico tools predict deleterious outcome. No functional studies reporting an impact of the variant on the protein function were published at the time of evaluation. The variant is absent from control population dataset of ExAC, but is present at a low frequency in the gnomAD dataset (1/30980 chrs tested; observed in Latino cohort). The variant has not, to our knowledge, been reported in affected individuals or cited by a reputable database/clinical laboratory. Taking together, the variant was classified as VUS until more information becomes available.
Invitae RCV000630033 SCV000750989 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-29 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 574 of the PMS2 protein (p.Pro574Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 480301). 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 serine amino acid residue is 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 and their clinical significance is uncertain. 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.
Color Health, Inc RCV000566855 SCV000913068 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-19 criteria provided, single submitter clinical testing
GeneDx RCV000588325 SCV001820525 uncertain significance not provided 2019-10-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

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