ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2714C>T (p.Thr905Ile) (rs267608022)

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 RCV000131745 SCV000186786 likely benign Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Invitae RCV000235233 SCV000259987 likely benign not provided 2019-02-26 criteria provided, single submitter clinical testing
GeneDx RCV000235233 SCV000292627 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2714C>T at the cDNA level, p.Thr905Ile (T905I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been identified in at least one individual undergoing multi-gene hereditary cancer panel testing, and at least one individual of Ashkenazi Jewish ancestry undergoing whole genome sequencing from a cohort of control subjects from two non-cancer related studies (Carmi 2014, Mu 2016). Hampel et al. (2018) favor MSH2 Thr905Ile to be a benign germline variant, as they observed it in a colon cancer in the allele that was lost in the tumor. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MSH2 Thr905Ile as a variant of uncertain significance (Thompson 2014). MSH2 Thr905Ile was observed at an allele frequency of 0.15% (15/10,132) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located in the helix-turn-helix domain and within the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, 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 MSH2 Thr905Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131745 SCV000685070 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781552 SCV000919686 uncertain significance not specified 2018-01-24 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2714C>T (p.Thr905Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Multiple studies using computational tools predicted variant as benign (Ali_2012, Niroula_2015). This variant was found in 22/276632 control chromosomesc (gnomAD), predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.00148 (15/10132). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. This variant has not been reported in affected individuals via publications; nor has it been evaluated for functional impact via in vitro/vivo studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/uncertain significance. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available.

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.