ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2503A>G (p.Asn835Asp) (rs41295296)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130169 SCV000185005 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000198710 SCV000254410 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 835 of the MSH2 protein (p.Asn835Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs41295296, ExAC 0.001%). This variant has been reported in individuals affected with endometrial and colorectal cancer (PMID: 16885385, 18033691, 21671081). ClinVar contains an entry for this variant (Variation ID: 141585). 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 RCV000520077 SCV000616787 uncertain significance not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2503A>G at the cDNA level, p.Asn835Asp (N835D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant was observed in at least two individuals with microsatellite unstable tumors, one with colon cancer who also harbored a second MSH2 missense variant, and another with endometrial cancer (Samowitz 2001, Hampel 2006). On functional interrogation, MSH2 Asn835Asp demonstrated mismatch repair proficiency in mouse embryonic stem cells (Houlleberghs 2016). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Asn835Asp is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Asn835Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000130169 SCV000906780 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing

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