Submissions for variant NM_000251.2(MSH2):c.2517T>A (p.His839Gln) (rs267608016)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524391	SCV000254411	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with glutamine at codon 839 of the MSH2 protein (p.His839Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs267608016, ExAC 0.001%). This variant has been reported in individuals affected with Lynch Syndrome (PMID: 18561205) and colorectal cancer (PMID: 18383312). ClinVar contains an entry for this variant (Variation ID: 90991). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and an algorithm developed specifically for the MSH2 gene (PMID: 18383312) all suggest that this missense change is likely to be tolerated, although these predictions have not been confirmed by published functional 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.
Ambry Genetics	RCV000216575	SCV000275133	likely benign	Hereditary cancer-predisposing syndrome	2019-03-28	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx	RCV000479296	SCV000567949	uncertain significance	not provided	2018-02-05	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2517T>A at the cDNA level, p.His839Gln (H839Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAT>CAA). This variant was observed in a familial colorectal cancer patient (Chao 2008). An ex vivo minigene assay performed by Tournier et al. (2008) did not show any effect of this variant on splicing, ruling out aberrant splicing as a possible mechanism of pathogenicity. MSH2 His839Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 His839Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color	RCV000216575	SCV000904009	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-06	criteria provided, single submitter	clinical testing

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