ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1828C>T (p.His610Tyr) (rs267607980)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163537 SCV000214095 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000163537 SCV000690022 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-21 criteria provided, single submitter clinical testing
GeneDx RCV000657098 SCV000568955 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1828C>T at the cDNA level, p.His610Tyr (H610Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 His610Tyr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 His610Tyr occurs at a position that is not conserved and is located in the Lever domain and the region of interaction with EXO1 (L?tzen 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 His610Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000484226 SCV000595833 uncertain significance not specified 2016-11-18 criteria provided, single submitter clinical testing
Invitae RCV000794229 SCV000933623 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-11 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 610 of the MSH2 protein (p.His610Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 184308). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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