ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.942+1G>T (rs587779193)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076752 SCV000107790 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000491583 SCV000580575 pathogenic Hereditary cancer-predisposing syndrome 2019-02-18 criteria provided, single submitter clinical testing The c.942+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 in the MSH2 gene. This alteration was identified in one Danish kindred suspicious for hereditary colorectal cancer (Nilbert M, Fam. Cancer 2009 ; 8(1):75-83). In addition, this alteration has been identified in patients with Lynch syndrome associated cancers whose tumors demonstrated loss of MSH2 and MSH6 protein on IHC analysis (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence experimental is unavailable. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Color Health, Inc RCV000491583 SCV000908286 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing
Invitae RCV000816442 SCV000956952 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-08-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Lynch syndrome (PMID: 18566915, 27601186). ClinVar contains an entry for this variant (Variation ID: 91247). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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.