Submissions for variant NM_000251.2(MSH2):c.599T>A (p.Val200Asp) (rs587779167)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076652	SCV000107687	pathogenic	Lynch syndrome I	2014-10-10	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Invitae	RCV000811653	SCV000951929	uncertain significance	Hereditary nonpolyposis colon cancer	2018-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine with aspartic acid at codon 200 of the MSH2 protein (p.Val200Asp). The valine residue is moderately conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91148). 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.