Submissions for variant NM_000179.2(MSH6):c.1793A>G (p.Lys598Arg) (rs587779919)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759845	SCV000149293	uncertain significance	not provided	2016-08-11	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1793A>G at the cDNA level, p.Lys598Arg (K598R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has been observed in at least one individual with breast cancer (Tung 2016). MSH6 Lys598Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH6 Lys598Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in domain II of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Lys598Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000168326	SCV000219013	uncertain significance	Hereditary nonpolyposis colon cancer	2018-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with arginine at codon 598 of the MSH6 protein (p.Lys598Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 127565). 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 arginine 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.
Genetic Services Laboratory, University of Chicago	RCV000115384	SCV000595858	uncertain significance	not specified	2017-03-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115384	SCV000601517	uncertain significance	not specified	2017-07-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565738	SCV000662354	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-24	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Counsyl	RCV000663315	SCV000786584	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2018-05-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759845	SCV000889460	uncertain significance	not provided	2017-07-13	criteria provided, single submitter	clinical testing
Color	RCV000565738	SCV000911465	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-16	criteria provided, single submitter	clinical testing