ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2634G>C (p.Glu878Asp) (rs63751624)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076524 SCV000107554 uncertain significance Lynch syndrome 2018-06-13 reviewed by expert panel curation G>non-G at last base of exon with first 6 intronic bases not GTRRGT; Insufficient evidence
Invitae RCV000697249 SCV000825849 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-06-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 878 of the MSH2 protein (p.Glu878Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant also falls at the last nucleotide of exon 15 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals suspected of having Lynch syndrome (PMID: 18566915, 11208710, 25648859). It has also been observed to segregate with Lynch syndrome-associated cancers in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 91022). Experimental studies have shown that this missense change results in reduced MSH2 protein levels and high microsatellite slippage (PMID: 26951660). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.2634G>A) has been determined to be pathogenic (PMID: 23523604, 21778331, 21791569). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Color RCV000772325 SCV000905443 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 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.