ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2296A>G (p.Ile766Val) (rs374399939)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165690 SCV000216428 uncertain significance Hereditary cancer-predisposing syndrome 2014-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000165690 SCV000690061 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-22 criteria provided, single submitter clinical testing
GeneDx RCV000766654 SCV000293211 uncertain significance not provided 2017-05-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2296A>G at the cDNA level, p.Ile766Val (I766V) 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 being pathogenic or benign. MSH2 Ile766Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile766Val occurs at a position that is conserved across species and is located within the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile766Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000798203 SCV000937805 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 766 of the MSH2 protein (p.Ile766Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs374399939, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 186151). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202197 SCV000257174 uncertain significance not specified no assertion criteria provided research

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