ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3845C>A (p.Thr1282Asn) (rs876660361)

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
Ambry Genetics RCV000218648 SCV000277727 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
Invitae RCV000462482 SCV000551114 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 1282 of the MSH6 protein (p.Thr1282Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 233369). 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: "Benign"; Align-GVGD: "Class C55"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000589207 SCV000568950 uncertain significance not provided 2017-10-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3845C>A at the cDNA level, p.Thr1282Asn (T1282N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr1282Asn was not observed at a significant frequency in large population cohorts (Lek 2016). Since Threonine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MSH6 Thr1282Asn occurs at a position that is conserved across species and is located in 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 evidence, it is unclear whether MSH6 Thr1282Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000487307 SCV000601589 uncertain significance not specified 2017-04-24 criteria provided, single submitter clinical testing
Color RCV000218648 SCV000685453 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589207 SCV000695894 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3845C>A (p.Thr1282Asn) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120858 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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.