Submissions for variant NM_000251.2(MSH2):c.565G>A (p.Ala189Thr) (rs63750821)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236727	SCV000292618	uncertain significance	not provided	2017-12-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.565G>A at the cDNA level, p.Ala189Thr (A189T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ala189Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ala189Thr is located in the connector domain (L?tzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Ala189Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000691636	SCV000819422	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 189 of the MSH2 protein (p.Ala189Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs63750821, 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: 245646). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236727	SCV000888223	uncertain significance	not provided	2018-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024381	SCV001186385	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-04	criteria provided, single submitter	clinical testing	Insufficient evidence

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