ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1760-1G>A (rs587779110)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076272 SCV000107297 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
GeneDx RCV000481985 SCV000568628 likely pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1760-1G>A or IVS11-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 11 of the MSH2 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one proband meeting Amsterdam criteria for Lynch syndrome (Hu 2011). Based on the currently available information, we consider MSH2 c.1760-1G>A to be a likely pathogenic variant.
Ambry Genetics RCV000491462 SCV000580446 pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing The c.1760-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 12 of the MSH2 gene. This mutation was reported in a family with HNPCC/Lynch syndrome meeting Amsterdam criteria (Hu P et al. Ann. Clin. Lab. Sci. 2011;41(4):321-30). It has also been detected in multiple individuals with colorectal cancers that demonstrated absent MSH2 and MSH6 protein expression on immunohistochemistry (IHC) (Barrow E et al. Histopathology 2010 Feb;56(3):331-44; Ambry internal data). 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.
Invitae RCV000546853 SCV000625306 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 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 two individuals affected with Lynch syndrome (PMID: 20459533, 22166501). ClinVar contains an entry for this variant (Variation ID: 90773). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000076272 SCV000887423 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.1760-1G>A has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Color Health, Inc RCV000491462 SCV000908316 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000076272 SCV000966940 likely pathogenic Lynch syndrome 2017-12-05 criteria provided, single submitter clinical testing The c.1760-1G>A variant in MSH2 has been reported in 1 individual with MSH2-asso ciated cancer (Hu et al. 2011) and was absent from large population studies. Thi s variant occurs in the invariant region (+/- 1,2) of the splice consensus seque nce and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the MSH2 gene is an established diseas e mechanism in Lynch syndrome. In addition, this variant was classified as likel y pathogenic on Sept 13, 2013 by the ClinGen-approved InSiGHT expert panel (Clin Var SCV000107297.2). In summary, although additional studies are required to ful ly establish its clinical significance, the c.1760-1G>A variant is likely pathog enic. ACMG/AMP Criteria applied: PVS1; PM2.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481985 SCV001134345 pathogenic not provided 2019-05-16 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient in literature, and not found in general population data.

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