ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2260A>T (p.Thr754Ser) (rs757268664)

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
Ambry Genetics RCV000221755 SCV000273102 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000221755 SCV000903534 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780438 SCV000917687 uncertain significance not specified 2018-01-26 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2260A>T (p.Thr754Ser) variant involves the alteration of a conserved nucleotide that leads to a missense change in the DNA mismatch repair protein MutS, C-terminal domain that is comprised of the ATPase domain and the HTH (helix-turn-helix) domain, the latter being involved in dimer contacts (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these predictions have not been confirmed by published functional studies. This variant was found in 2/246192 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). 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. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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.
Invitae RCV000464199 SCV000548248 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 754 of the MSH2 protein (p.Thr754Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs757268664, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 229770). 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 disruptive, 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.