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 The p.P622R variant (also known as c.1865C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1865. The proline at codon 622 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in an individual with clinical features of Lynch syndrome (Ambry internal data). This alteration was also identified as somatic in an endometrial tumor that displayed high microsatellite instability (MSI-H) with loss of MSH2 as well as MSH6 on immunohistochemistry (IHC) and a germline likely pathogenic variant in MSH2 was determined to be in trans (Ambry internal data). A pathogenic mutation (p.P622L) at the same codon has been reported to segregate with disease in families that met Amsterdam I/II criteria for Lynch syndrome and results from tumor testing for these individuals showed absent MSH2/MSH6 on IHC and/or MSI-H (Leach FS et al. Cell 1993 Dec;75:1215-25; Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Arnold S et al. Hum. Mutat., 2009 May;30:757-70). Also, numerous studies in mammalian and yeast systems have demonstrated that p.P622L results in reduced mismatch repair activity (Gammie AE et al. Genetics 2007 Oct;177:707-21; Lützen A et al. Mutat. Res. 2008 Oct;645:44-55; Mastrocola AS et al. Hum. Mutat. 2010 Oct;31:E1699-708; Wielders EA et al. Hum. Mutat. 2011 Apr;32:389-96; Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 colorectal neoplasms 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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