ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.62G>T (p.Arg21Leu) (rs730881760)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485060 SCV000567890 uncertain significance not provided 2015-09-11 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.62G>T at the cDNA level, p.Arg21Leu (R21L) at the protein level, and results in the change of an Arginine to a Leucine (CGC>CTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Arg21Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Arg21Leu occurs at a position that is conserved in mammals and is located in the mismatch binding domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Arg21Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000552453 SCV000625446 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 21 of the MSH2 protein (p.Arg21Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Universal Mutation Database (UMD) (PMID: 22144684). However, the UMD database contains both benign and pathogenic variants, and the interpretation of this particular variant is not necessarily informed by its presence in this database. 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000572631 SCV000662318 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000572631 SCV000909044 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing

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