ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1191A>T (p.Gln397His) (rs768694189)

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
University of Washington Department of Laboratory Medicine,University of Washington RCV000210074 SCV000266189 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000482758 SCV000571926 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1191A>T at the cDNA level, p.Gln397His (Q397H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAT). This variant has been reported in an individual with liver cancer and polyps that demonstrated normal mismatch repair immunohistochemistry (Shirts 2016). MSH2 Gln397His was not observed in large population cohorts (Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln397His occurs at a position that is not conserved and is located within the Lever domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 2008). 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 MSH2 Gln397His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568248 SCV000662254 likely benign Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000629900 SCV000750856 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 397 of the MSH2 protein (p.Gln397His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with liver cancer and polyps (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224575). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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.
Color RCV000568248 SCV000905082 likely benign Hereditary cancer-predisposing syndrome 2016-12-12 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.