ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2650A>T (p.Ile884Phe) (rs774732579)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236021 SCV000294098 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2650A>T at the cDNA level, p.Ile884Phe (I884F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile884Phe was not observed in large population cohorts (Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile884Phe occurs at a position that is conserved across species and is present in the helix-turn-helix domain and region of interaction with MSH6 and MSH3 (L?tzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile884Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000566067 SCV000669804 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000804993 SCV000944934 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 884 of the MSH2 protein (p.Ile884Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs774732579, 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: 246511). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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