ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1865C>G (p.Pro622Arg) (rs28929483)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256112 SCV000322563 likely pathogenic not provided 2018-03-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1865C>G at the cDNA level, p.Pro622Arg (P622R) at the protein level, and results in the change of a Proline to an Arginine (CCA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, a different variant at the same position, the semi-conservative change MSH2 Pro622Leu, has been reported in individuals with Lynch syndrome, associated with functional defects in vitro, and classified by the International Society for Gastrointestinal Tumours Incorporated (InSiGHT) as pathogenic (Leach 1993, Heinen 2002, Jenkins 2002, Southey 2005, Belvederesi 2008, Lutzen 2008, Arnold 2009, Mastrocola 2010, Drost 2012, Walsh 2012, Rosty 2014, Thompson 2014, Houlleberghs 2016). MSH2 Pro622Arg 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 Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Pro622Arg occurs at a position that is conserved across species and is located in the ATPase domain and the region of interaction with EXO1 (Lützen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Pro622Arg to be a likely pathogenic variant.
Ambry Genetics RCV000491622 SCV000580538 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506471 SCV000601444 uncertain significance not specified 2017-04-27 criteria provided, single submitter clinical testing
Invitae RCV000629692 SCV000750648 uncertain significance Hereditary nonpolyposis colon cancer 2017-09-21 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 622 of the MSH2 protein (p.Pro622Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported an individual affected with Lynch syndrome in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 265573). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Pro622Leu) has been determined to be pathogenic (PMID: 7717919, 8261515, 17720936, 21309037, 22102614, 26951660). This suggests that the proline residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. 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.

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