Submissions for variant NM_000251.2(MSH2):c.1530G>C (p.Gln510His) (rs587782355)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235175	SCV000211186	uncertain significance	not provided	2018-08-02	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1530G>C at the cDNA level, p.Gln510His (Q510H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has been reported in an individual with endometrial cancer (Ring 2016). MSH2 Gln510His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the clamp domain and in the region of interaction with MSH6 and MSH3 (Guerrette 1998, 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 Gln510His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160591	SCV000214490	uncertain significance	Hereditary cancer-predisposing syndrome	2017-11-03	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae	RCV000548522	SCV000625279	uncertain significance	Hereditary nonpolyposis colon cancer	2018-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with histidine at codon 510 of the MSH2 protein (p.Gln510His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (rs587782355, ExAC no frequency). This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 182563). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color	RCV000160591	SCV000911171	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-13	criteria provided, single submitter	clinical testing

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