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 colorectal neoplasms 2019-11-04 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 observed in an individual with colorectal cancer (Invitae). However, in that individual pathogenic allele[s] were also identified in MSH2, which suggests that this c.62G>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 419807). 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.
Ambry Genetics RCV000572631 SCV000662318 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-29 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000572631 SCV000909044 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-03 criteria provided, single submitter clinical testing

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