ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.190G>C (p.Ala64Pro) (rs587779921)

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 RCV000759850 SCV000149295 uncertain significance not provided 2014-02-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.190G>C at the cDNA level, p.Ala64Pro (A64P) at the protein level, and results in the change of an Alanine to a Proline (GCG>CCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala64Pro 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. The MSH6 Ala64Pro variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The variant occurs at a position that is moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on currently available information, it is unclear whether MSH6 Ala64Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000214011 SCV000274033 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000214011 SCV000685238 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759850 SCV000889467 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000759850 SCV001152286 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Invitae RCV001041141 SCV001204741 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 64 of the MSH6 protein (p.Ala64Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 127567). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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.