ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2030C>G (p.Thr677Arg) (rs876660711)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215510 SCV000278353 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000462315 SCV000548317 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 677 of the MSH2 protein (p.Thr677Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with rectal cancer (PMID: 22086678, 27432916). ClinVar contains an entry for this variant (Variation ID: 233888). 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.
GeneDx RCV000484436 SCV000569536 uncertain significance not provided 2016-11-16 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2030C>G at the cDNA level, p.Thr677Arg (T677R) at the protein level, and results in the change of a Threonine to an Arginine (ACA>AGA). This variant was observed in the germline of an individual with early-onset rectal cancer whose tumor was mismatch repair deficient on immunohistochemistry (de Rosa 2016). MSH2 Thr677Arg was also observed in another individual with rectal cancer whose tumor demonstrated microsatellite instability (MSI-H) and normal protein expression on immunohistochemistry (Bartley 2012). MSH2 Thr677Arg 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 Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Thr677Arg occurs at a position that is conserved across species and is located in the ATPase domain (Lutzen 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 Thr677Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.

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