ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1418C>T (p.Ser473Leu) (rs63751403)

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 RCV000218562 SCV000277896 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000627720 SCV000284111 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 473 of the MSH2 protein (p.Ser473Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs63751403, ExAC 0.01%). This variant has been reported in an individual affected with Lynch syndrome (PMID: 12658575). However, a pathogenic allele was identified in the MSH2 gene, which suggests that this c.1418C>T substitution in MSH2 was not the primary cause of disease in this individual. ClinVar contains an entry for this variant (Variation ID: 90660). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000482094 SCV000565193 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1418C>T at the cDNA level, p.Ser473Leu (S473L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). Although this variant was observed in a family that met Lynch syndrome Amsterdam Criteria, the family also had the MSH2 pathogenic variant c.387_388delTC, accounting for the reported family history (Wagner 2003). MSH2 Ser473Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Clamp domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 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 Ser473Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000218562 SCV000903754 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148630 SCV000190345 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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.