ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3257C>A (p.Pro1086His) (rs780345806)

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
GeneDx RCV000482150 SCV000571204 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3257C>A at the cDNA level, p.Pro1086His (P1086H) at the protein level, and results in the change of a Proline to a Histidine (CCC>CAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Pro1086His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase 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 Pro1086His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000560746 SCV000624837 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-22 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 1086 of the MSH6 protein (p.Pro1086His). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs780345806, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 421879). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000570886 SCV000676109 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000570886 SCV000685374 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-29 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.