ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1211C>G (p.Pro404Arg) (rs536111818)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132334 SCV000187422 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168006 SCV000218657 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 404 of the PMS2 protein (p.Pro404Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs536111818, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals with suspected Lynch syndrome, and an individual affected with harmartomatous polyposis (PMID: 19690142, 26437257, 27146957). ClinVar contains an entry for this variant (Variation ID: 142875). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional 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 RCV000479344 SCV000565842 uncertain significance not provided 2018-12-17 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1211C>G at the cDNA level, p.Pro404Arg (P404R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). This variant was observed in individuals with a personal and/or family history suspicious for Lynch syndrome (Mueller 2009, Carneiro da Silva 2015, Yurgelun 2015). Colorectal tumor analysis from two of these individuals revealed either microsatellite instability or absence of PMS2 protein on immunohistochemistry (Mueller 2009, Carneiro da Silva 2015). PMS2 Pro404Arg was also observed in an individual with one juvenile polyp (Jelsig 2016). Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Pro404Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132334 SCV000686108 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000479344 SCV000806167 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479344 SCV001134576 uncertain significance not provided 2019-06-20 criteria provided, single submitter clinical testing
Mendelics RCV000987836 SCV001137305 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193252 SCV001361980 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1211C>G (p.Pro404Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 249858 control chromosomes. The observed variant frequency is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Non-Polyposis Colon Cancer phenotype (7.1e-05), however this data should be cautiously interpreted as PMS2 has highly homologous pseudogenes. c.1211C>G has been reported in the literature in individuals with suspected Lynch Syndrome and LS-associated cancers as well as breast cancer (daSilva_2015, Jelsig_2016, Kraus_2015, Mueller_2009, Rossi_2017, Yurgelun_2015), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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