ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3974A>T (p.Lys1325Met) (rs876658189)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215262 SCV000273567 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215262 SCV000537550 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000485930 SCV000566508 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3974A>T at the cDNA level, p.Lys1325Met (K1325M) at the protein level, and results in the change of a Lysine to a Methionine (AAG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys1325Met 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 Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Lys1325Met occurs at a position that is not conserved and is located within the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Lys1325Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000697066 SCV000825656 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with methionine at codon 1325 of the MSH6 protein (p.Lys1325Met). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 230130). 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.

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.