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 2018-12-28 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 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000491263 SCV000684952 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588411 SCV000696220 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1600C>T (p.Arg534Cys) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index) along with ESE finder predicting the variant to eliminate splice enhancer SRp55) binding site and therefore and impact on splicing. This prediction was confirmed by in vitro studies demonstrating the variant to result in decreased exon inclusion (Lastella_2006). The variant was found in 1/121298 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). To our knowledge, it was not reported in affected individuals with strong evidence for causality such as co-segregation with the disease at the time of classification. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is 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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