ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1144C>T (p.Arg382Cys) (rs752373431)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214618 SCV000276498 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409794 SCV000489635 uncertain significance Lynch syndrome I 2016-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000480571 SCV000566392 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1144C>T at the cDNA level, p.Arg382Cys (R382C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Arg382Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Lever domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 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 Arg382Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000546544 SCV000625229 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 382 of the MSH2 protein (p.Arg382Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs752373431, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 232371). 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. 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.
Color RCV000214618 SCV000689955 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-04 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761006 SCV000890921 uncertain significance Ewing sarcoma of soft tissue 2016-03-21 no assertion criteria provided clinical testing

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