ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1796T>C (p.Leu599Ser) (rs747504492)

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
University of Washington Department of Laboratory Medicine,University of Washington RCV000210095 SCV000266195 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000219087 SCV000273774 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000520524 SCV000617005 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1796T>C at the cDNA level, p.Leu599Ser (L599S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). This variant was observed in at least one individual with early-onset breast cancer (Shirts 2016). MSH2 Leu599Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Lever domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Leu599Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000530644 SCV000625318 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 599 of the MSH2 protein (p.Leu599Ser). The leucine residue is weakly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs747504492, ExAC 0.002%). This variant has been reported in an individual affected with breast cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224577). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000219087 SCV000684977 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Counsyl RCV000662912 SCV000785841 uncertain significance Lynch syndrome I 2017-12-18 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.