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

Total submissions: 5

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	Insufficient or conflicting evidence
Invitae	RCV000548522	SCV000625279	uncertain significance	Hereditary nonpolyposis colon cancer	2019-12-07	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	2020-01-15	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001137232	SCV001297152	uncertain significance	Lynch syndrome I	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.