ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.980C>G (p.Thr327Ser) (rs369568820)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164123 SCV000214738 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000204780 SCV000260205 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 327 of the MSH6 protein (p.Thr327Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs369568820, ExAC 0.003%). This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 184803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), all suggest that this missense change is likely to be tolerated. The serine 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.
GeneDx RCV000479969 SCV000568902 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.980C>G at the cDNA level, p.Thr327Ser (T327S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has been observed in at least two individuals with epithelial ovarian cancer and another with pancreatic cancer (Pal 2012, Grant 2015). MSH6 Thr327Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. MSH6 Thr327Ser occurs at a position that is not conserved and is located within the nuclear localization signals (Gassman 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Thr327Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479969 SCV000889512 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing
Color RCV000164123 SCV000911932 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-16 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.