ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1489A>G (p.Ile497Val) (rs755501968)

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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 RCV000219613 SCV000274152 likely benign Hereditary cancer-predisposing syndrome 2019-02-22 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
GeneDx RCV000483517 SCV000567758 uncertain significance not provided 2018-04-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1489A>G at the cDNA level, p.Ile497Val (I497V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile497Val was 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 interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 2008, Kansikas 2011). While protein-based in silico analyses predict that this variant is unlikely to alter protein structure or function, multiple splicing models predict that this variant may create a cryptic splice donor site upstream of the natural splice donor, leading to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH2 Ile497Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630079 SCV000751035 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 497 of the MSH2 protein (p.Ile497Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs755501968, ExAC 0.006%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 230562). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Color RCV000219613 SCV000908304 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483517 SCV001134339 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing
Mendelics RCV000986672 SCV001135732 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing

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