ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3772C>G (p.Gln1258Glu) (rs63750554)

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
Invitae RCV000227470 SCV000283822 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 1258 of the MSH6 protein (p.Gln1258Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs63750554, ExAC 0.07%). This variant has been observed in individuals with suspected Lynch syndrome, one of whom was also reported to carry an unspecified pathogenic variant (PMID: 29575718, 28874130, 28932927, 31386297). ClinVar contains an entry for this variant (Variation ID: 237198). 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.
GeneDx RCV000766490 SCV000569546 uncertain significance not provided 2016-09-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3772C>G at the cDNA level, p.Gln1258Glu (Q1258E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gln1258Glu was not observed at significant allele frequency in the NHLBI Exome Sequencing Project or 1000 Genomes. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Gln1258Glu occurs at a position that is not conserved and is located within the MutS domain V (Terui 2013). 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 Gln1258Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491197 SCV000580142 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479785 SCV000601585 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing
Color RCV000491197 SCV000905458 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000479785 SCV001360534 uncertain significance not specified 2019-07-26 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3772C>G (p.Gln1258Glu) results in a conservative amino acid change located in the C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251214 control chromosomes, predominantly at a frequency of 0.00049 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3772C>G has been reported in the literature in individuals affected with Lynch Syndrome (Rossi_2017, Soares_2018, Schneider_2018) and familial breast cancer (Wang_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant (after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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.