Submissions for variant NM_000251.2(MSH2):c.896A>G (p.Tyr299Cys) (rs1558464315)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000687665	SCV000815249	uncertain significance	Hereditary nonpolyposis colon cancer	2018-04-04	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 299 of the MSH2 protein (p.Tyr299Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. 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. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
University of Washington Department of Laboratory Medicine,University of Washington	RCV000758588	SCV000887337	likely benign	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.896A>G has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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