Submissions for variant NM_000179.2(MSH6):c.3220A>G (p.Met1074Val) (rs730881804)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587626	SCV000211315	uncertain significance	not provided	2018-08-14	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3220A>G at the cDNA level, p.Met1074Val (M1074V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in an individual with suspected Hereditary Nonpolyposis Colorectal Cancer whose tumor demonstrated decreased, but not absent, MSH6 expression on immunohistochemistry (Okkels 2012). MSH6 Met1074Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the lever 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 Met1074Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000232219	SCV000283792	uncertain significance	Hereditary nonpolyposis colon cancer	2018-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 1074 of the MSH6 protein (p.Met1074Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs730881804, ExAC 0.001%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 22495361). ClinVar contains an entry for this variant (Variation ID: 182645). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	RCV000562784	SCV000662419	uncertain significance	Hereditary cancer-predisposing syndrome	2017-06-29	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
Color	RCV000562784	SCV000690331	uncertain significance	Hereditary cancer-predisposing syndrome	2018-10-18	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000587626	SCV000695844	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3220A>G (p.Met1074Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome, and Met1074 is located in the core domain of the DNA mismatch repair protein Msh6. This variant was found in 1/121320 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, one clinical diagnostic laboratory classified this variant as a VUS. The variant was identified in one patient with a colon adenocarcinoma and suspected HNPCC, and shown to have reduced MSH6 expression via immunohistochemistry; however, no data was provided to conclusively prove causality (Okkels_Appl Immunohistochem Mol Morphol_2012). Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.