ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1828C>A (p.His610Asn) (rs267607980)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000428720 SCV000532783 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing The H610N variant in the MSH2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. An ex vivo minigene assay performed by Tournier et al. (2008) did not show any effect of MSH2 His610Asn on splicing, ruling out aberrant splicing as the possible mechanism of pathogenicity. The H610N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The H610N variant occurs at a position that is not conserved and is located in the lever domain and a region of interaction with MSH3/6 and EXO1 (Lützen et al., 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider H610N to be a variant of uncertain significance.
Counsyl RCV000663086 SCV000786175 uncertain significance Lynch syndrome I 2018-03-19 criteria provided, single submitter clinical testing
Invitae RCV000707667 SCV000836772 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 610 of the MSH2 protein (p.His610Asn). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual from a family affected with Lynch syndrome (PMID: 18561205). ClinVar contains an entry for this variant (Variation ID: 90797). This variant has been reported not to substantially affect MSH2 protein function (PMID: 30998989). 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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