ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1360A>G (p.Ile454Val) (rs587781627)

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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 RCV000129729 SCV000184534 likely benign Hereditary cancer-predisposing syndrome 2016-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761179 SCV000891095 uncertain significance B lymphoblastic leukemia lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) 2017-04-26 no assertion criteria provided clinical testing
Color RCV000129729 SCV000908302 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000588274 SCV000565191 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1360A>G at the cDNA level, p.Ile454Val (I454V) 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 Ile454Val was not observed at a significant frequency in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile454Val occurs at a position that is conserved across species and is located in the lever domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, 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 Ile454Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588274 SCV000696208 uncertain significance not provided 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1360A>G (p.Ile454Val) variant causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 119816 control chromosomes. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000460057 SCV000548202 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 454 of the MSH2 protein (p.Ile454Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 141281). 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.

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