ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1967A>C (p.Tyr656Ser) (rs185356145)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479030 SCV000567230 uncertain significance not provided 2015-07-16 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1967A>C at the cDNA level, p.Tyr656Ser (Y656S) at the protein level, and results in the change of a Tyrosine to a Serine (TAC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Tyr656Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Tyr656Ser occurs at a position that is not conserved and is located in the ATPase domain and the region of interaction with EXO1 (Lutzen 2008, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH2 Tyr656Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000688258 SCV000815863 uncertain significance Hereditary nonpolyposis colon cancer 2019-07-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 656 of the MSH2 protein (p.Tyr656Ser). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and serine. 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: 419432). 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.
Ambry Genetics RCV001013864 SCV001174499 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001013864 SCV001356760 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing

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