ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1813G>A (p.Val605Ile) (rs730881777)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212610 SCV000211237 uncertain significance not provided 2018-03-28 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1813G>A at the cDNA level, p.Val605Ile (V605I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Val605Ile was not observed in large population cohorts (Lek 2016). This variant is located in the Lever domain and the regions of interaction with MSH6, MSH3, and EXO1 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Val605Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160636 SCV000217664 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000462601 SCV000548251 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 605 of the MSH2 protein (p.Val605Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs730881777, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182596). 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 tolerated, 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.
Mendelics RCV000708835 SCV000837840 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000160636 SCV000906436 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing
Mendelics RCV000986680 SCV001135746 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing

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