Submissions for variant NM_000179.2(MSH6):c.3992G>A (p.Arg1331Gln) (rs184131049)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482748	SCV000568116	uncertain significance	not provided	2018-07-12	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3992G>A at the cDNA level, p.Arg1331Gln (R1331Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as being a pathogenic or benign germline variant. MSH6 Arg1331Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the MSH2 binding site and the ATPase domain (Warren 2007, 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 MSH6 Arg1331Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000491185	SCV000580208	uncertain significance	Hereditary cancer-predisposing syndrome	2017-05-31	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae	RCV000707566	SCV000836667	uncertain significance	Hereditary nonpolyposis colon cancer	2018-08-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 1331 of the MSH6 protein (p.Arg1331Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 419915). 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 glutamine 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482748	SCV001134450	uncertain significance	not provided	2018-10-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000986744	SCV001135856	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2019-05-28	criteria provided, single submitter	clinical testing

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