ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1686G>C (p.Glu562Asp) (rs786203850)

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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 RCV000167337 SCV000218188 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000464235 SCV000548323 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 562 of the MSH2 protein (p.Glu562Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 187594). 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.
GeneDx RCV000482582 SCV000565196 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1686G>C at the cDNA level, p.Glu562Asp (E562D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu562Asp 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 Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. MSH2 Glu562Asp occurs at a position that is conserved across species and is located in the lever domain and region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Glu562Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.

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