ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2551C>G (p.Leu851Val) (rs267608015)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129900 SCV000184718 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000236960 SCV000293942 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2551C>G at the cDNA level, p.Leu851Val (L851V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant was reported in an individual with an ovarian, peritoneal, or fallopian tube cancer whose tumor demonstrated no loss of heterozygosity or microsatellite stability, and normal immunohistochemistry for all four mismatch repair proteins (Walsh 2011). MSH2 Leu851Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu851Val occurs at a position that is conserved across species and is located in the ATPase domain (Lützen 2008, Kansikas 2011). 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 Leu851Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000129900 SCV000685054 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-18 criteria provided, single submitter clinical testing
Invitae RCV000698893 SCV000827582 uncertain significance Hereditary nonpolyposis colon cancer 2019-08-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 851 of the MSH2 protein (p.Leu851Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine 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: 141396). 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.

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