ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.97A>G (p.Thr33Ala) (rs63751107)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000684814 SCV000548275 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 33 of the MSH2 protein (p.Thr33Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs63751107, ExAC 0.009%). This sequence change has been observed in individuals affected with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 16395668). ClinVar contains an entry for this variant (Variation ID: 91268). 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 RCV000480593 SCV000568619 uncertain significance not provided 2017-02-08 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.97A>G at the cDNA level, p.Thr33Ala (T33A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant was observed in a family with clinical history consistent with Lynch syndrome (Auclair 2006). MSH2 Thr33Ala 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 Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Thr33Ala occurs at a position that is conserved across species and is located in the mismatch binding 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 Thr33Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565059 SCV000669761 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000565059 SCV000685146 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Mendelics RCV000076773 SCV000837813 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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