ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2634G>A (p.Glu878=) (rs63751624)

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
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076523 SCV000107553 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration leading to truncated protein: full inactivation of variant allele
Invitae RCV000791439 SCV000260754 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-30 criteria provided, single submitter clinical testing This sequence change affects codon 878 of the MSH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MSH2 protein. 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 and families affected with Lynch syndrome (LS) (PMID: 21778331, 23523604, Invitae), and shown to segregate with LS-associated cancers in several families (PMID: 21778331, Invitae). ClinVar contains an entry for this variant (Variation ID: 91021). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this silent change causes the out-of-frame skipping of exon 15 (PMID: 23523604). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491856 SCV000580401 pathogenic Hereditary cancer-predisposing syndrome 2019-04-04 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Last nucleotide of exon;Functionally-validated splicing mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000519129 SCV000617594 likely pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2634G>A at the cDNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 878, it is located at the last nucleotide of exon 15 and disrupts the naturalsplice donor site leading to abnormal splicing. RT-PCR studies have demonstrated that MSH2 c.2634G>A causescomplete skipping of exon 15 (Pérez-Cabornero 2013). This variant has been observed in a family meeting Amsterdamcriteria and was found to segregate with endometrial cancer in two family members. The proband's tumor displayedabsence of the MSH2 and MSH6 proteins and microsatellite instability (MSI-H) (Pérez-Cabornero 2011). MSH2c.2634G>A was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 GenomesConsortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 2634, is conserved acrossspecies. Based on currently available evidence, we consider this variant to be likely pathogenic
Integrated Genetics/Laboratory Corporation of America RCV001255522 SCV001431962 pathogenic Hereditary nonpolyposis colon cancer 2020-08-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2634G>A (p.Glu878Glu) alters a conserved nucleotide located at the last nucleotide of exon 15 adjacent to a canonical splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping on exon 15 (Perez-Cabornero_2013). The variant was absent in 251400 control chromosomes. c.2634G>A has been reported in the literature in individuals affected with Lynch Syndrome (example Perez-Cabornero_2011 and Katsidzira_2019). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic. An expert panel (InSight) has submitted clinical significance assessment for this variant as Pathogenic to ClinVar before 2014. Based on the evidence outlined above, the variant was 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.