ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
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 colon cancer 2018-11-08 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 Lines of evidence used in support of classification: Insufficient evidence
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 2018-08-29 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.