ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1145G>A (p.Arg382His) (rs267607947)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487066 SCV000567808 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1145G>A at the cDNA level, p.Arg382His (R382H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been reported in at least one individual with late-onset microsatellite unstable (MSI-H) rectal cancer (Jin 2008). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as a variant of uncertain significance (Thompson 2014). MSH2 Arg382His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Lever domain and within a region responsible for 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 Arg382His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568561 SCV000664841 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000568561 SCV000684908 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000663061 SCV000786122 uncertain significance Lynch syndrome I 2018-02-27 criteria provided, single submitter clinical testing
Invitae RCV000703497 SCV000832400 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 382 of the MSH2 protein (p.Arg382His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID: 18257912). ClinVar contains an entry for this variant (Variation ID: 90553). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be tolerated (PMID: 26333163). However, this prediction has not been confirmed by published functional studies and its 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.

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