Submissions for variant NM_000251.2(MSH2):c.1907C>T (p.Ala636Val) (rs63750279)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524367	SCV000548306	uncertain significance	Hereditary nonpolyposis colon cancer	2019-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 636 of the MSH2 protein (p.Ala636Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs63750279, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 90815). 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. 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. A different missense substitution at this codon (p.Ala636Pro) has been determined to be pathogenic (PMID: 12454801, 21419771, 23990280, 19101824). This suggests that the alanine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Color	RCV000583770	SCV000690028	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000583770	SCV001174193	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-06	criteria provided, single submitter	clinical testing	Insufficient evidence

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