ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2210+1G>A (rs267608002)

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) RCV000076423 SCV000107451 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000524382 SCV000548155 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 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 reported in the literature in individuals with early onset colorectal cancer (PMID: 18307539, 17189986), and in families with Lynch syndrome or suspected Lynch syndrome (PMID: 24710284, 12362047). ClinVar contains an entry for this variant (Variation ID: 90921). 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.
Ambry Genetics RCV000490900 SCV000580436 pathogenic Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing The c.2210+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the MSH2 gene. This alteration has previously been detected in multiple individuals with early-onset colorectal cancer whose tumors demonstrated microsatellite instability and deficient MSH2 immunostaining (Yan HL et al. Cancer Sci. 2008 Apr;99(4):770-80; Ambry internal data). In addition, another alteration at this location, c.2210+1G>C, has been identified in a Lynch syndrome kindred and reported to cause an out of frame deletion of exon 13 (Kámory E et al. Pathol. Oncol. Res. 2006;12(4):228-33; Kurzawski G et al. Clin. Genet. 2006 Jan;69(1):40-7). Using the BDGP and ESEfinder splice site prediction tools, the c.2210+1G>A alteration is predicted to abolish the native donor splice site; however, direct evidence 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.

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.