ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2551C>A (p.Leu851Ile) (rs267608015)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236323 SCV000293337 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2551C>A at the cDNA level, p.Leu851Ile (L851I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTT>ATT). This variant was observed within a Sinhalese family with Lynch syndrome-associated cancer (Yap 2009). MSH2 Leu851Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu851Ile is located in the ATPase domain (L?tzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain" due to insufficient evidence (Thompson 2014). Based on currently available evidence, it is unclear whether MSH2 Leu851Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance."
Counsyl RCV000410329 SCV000489510 uncertain significance Lynch syndrome I 2016-10-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491427 SCV000580606 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000552050 SCV000625386 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 851 of the MSH2 protein (p.Leu851Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs267608015, ExAC 0.01%). This variant has been reported in the literature in an individual affected with colorectal cancer or other Lynch syndrome associated cancer (PMID: 18726168). ClinVar contains an entry for this variant (Variation ID: 90998). Algorithms developed to predict the effect of missense changes on protein structure and function 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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