ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2647dup (p.Ile883fs) (rs63750084)

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 RCV000561651 SCV000662210 pathogenic Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000561651 SCV000905445 pathogenic Hereditary cancer-predisposing syndrome 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000657244 SCV000778974 pathogenic not provided 2019-04-22 criteria provided, single submitter clinical testing This duplication causes a frameshift which changes an Isoleucine to an Asparagine at codon 883, and creates a premature stop codon at position 16 of the new reading frame. Even though nonsense-mediateddecay is not expected to occur due to the position of the variant, it is significant since the last 52 amino acids are no longer translated correctly and are replaced by 15 incorrect amino acids. This variant is predicted to cause loss ofnormal protein function through protein truncation. MSH2 Ile883AsnfsX16 has been observed in individuals with apersonal and/or family history suggestive of Lynch syndrome, including an individual with colon cancer demonstrating microsatellite instability (Hampel 2005, Bonadona 2011). Additionally, Wielders et al. (2017) found that MSH2 variants lacking the c-terminus severely destabilize MSH2/MSH6 interaction and result in increased microsatellite instability. Based on the currently available information, we consider this duplication to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076533 SCV000107562 pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation This variant is before the cutoff (codon 888) and therefore Class 5
Invitae RCV000797824 SCV000937406 pathogenic Hereditary nonpolyposis colon cancer 2019-01-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH2 gene (p.Ile883Asnfs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with colorectal cancer (PMID: 15872200, 29967336). ClinVar contains an entry for this variant (Variation ID: 91031). While this variant is not expected to result in nonsense mediated decay, it is expected to disrupt nearly the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (disrupted residues Ile883-Thr934) (PMID: 9774676, 18822302, 17531815). Other variant(s) that disrupt this region (p.Leu888Cysfs*4) have been determined to be pathogenic (PMID: 9222765, 8640829, 21879275, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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.