ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1922G>A (p.Cys641Tyr) (rs786204110)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168044 SCV000218697 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 641 of the MSH2 protein (p.Cys641Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine 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: 188155). 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 disruptive, 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 RCV000483193 SCV000570463 uncertain significance not provided 2016-05-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1922G>A at the cDNA level, p.Cys641Tyr (C641Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Cys641Tyr 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 Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Cys641Tyr occurs at a position that is conserved across species and is located in ATPase domain as well as in the region of interaction with EXO1 (Lützen 2008, UniProt). 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 Cys641Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563020 SCV000669749 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-26 criteria provided, single submitter clinical testing Insufficient evidence

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