Submissions for variant NM_000179.2(MSH6):c.1633A>G (p.Lys545Glu) (rs1064793403)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479973	SCV000566031	uncertain significance	not provided	2016-10-04	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1633A>G at the cDNA level, p.Lys545Glu (K545E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has been observed in at least one individual with endometrial cancer (Le Gallo 2012). MSH6 Lys545Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Lys545Glu occurs at a position that is conserved across species and is located in the MSH2 binding site and domain II of the MutS domain (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Lys545Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000545794	SCV000624670	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with glutamic acid at codon 545 of the MSH6 protein (p.Lys545Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 418743). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant has uncertain impact on MSH6 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000574287	SCV000662416	uncertain significance	Hereditary cancer-predisposing syndrome	2017-11-07	criteria provided, single submitter	clinical testing	Insufficient evidence
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000659891	SCV000781788	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000765683	SCV000897025	uncertain significance	Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5	2018-10-31	criteria provided, single submitter	clinical testing
Color	RCV000574287	SCV000906723	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-07	criteria provided, single submitter	clinical testing

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