ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1786A>C (p.Asn596His) (rs1064794906)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484616 SCV000570186 uncertain significance not provided 2016-11-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1786A>C at the cDNA level, p.Asn596His (N596H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asn596His 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 Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Asn596His occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located within the lever domain and the region known for 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 evidence, it is unclear whether MSH2 Asn596His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001013177 SCV001173727 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-07 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001205685 SCV001376954 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 596 of the MSH2 protein (p.Asn596His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. 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: 421094). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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