ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1600C>T (p.Arg534Cys) (rs63750029)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524349 SCV000211917 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 534 of the MSH2 protein (p.Arg534Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs63750029, ExAC 0.01%). This variant has been reported in a family undergoing testing for Lynch syndrome (PMID: 18561205) as well as an individual with no personal or family history of colorectal cancer (PMID: 26344056). ClinVar contains an entry for this variant (Variation ID: 90707). Experimental studies are conflicting with regards to the effect of this missense change on mRNA splicing. One study showed a decrease in inclusion of exon 10 in a cell culture assay (PMID: 16995940), while a second study found no significant splicing changes associated with this variant in an ex vivo splicing assay (PMID: 18561205). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for mismatch repair genes (PMID: 22290698), suggest that this missense change is likely to be deleterious. However, 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.
Counsyl RCV000410514 SCV000487881 uncertain significance Lynch syndrome I 2015-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000588411 SCV000567089 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1600C>T at the cDNA level, p.Arg534Cys (R534C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in at least one individual reported to have HNPCC, but was also observed in a control population without personal or family history of colorectal cancer (Tournier 2008, Arora 2015). Mini-gene splicing assays have shown this variant to cause partial or complete skipping of exon 10 (Lastella 2006, Tournier 2008). The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classifies MSH2 Arg534Cys as a variant of uncertain clinical significance based on insufficient evidence (Thompson 2014). MSH2 Arg534Cyswas not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the clamp domain and the region of itneraction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Arg534Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491263 SCV000580434 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000491263 SCV000684952 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175346 SCV000696220 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1600C>T (p.Arg534Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. A functional study showed a decrease in inclusion of exon 10 in an in-vitro mini-gene assay perfromed in several cell lines (Lastella_2006). The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes. c.1600C>T has been reported in the literature in patients and controls (e.g.- Gorlov_2003, Arora_2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS- possibly pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000076204 SCV000887412 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.1600C>T has a 76.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588411 SCV000889419 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing

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