ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.793-1G>A (rs863225397)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491505 SCV000580598 pathogenic Hereditary cancer-predisposing syndrome 2018-07-19 criteria provided, single submitter clinical testing The c.793-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 5 of the MSH2 gene. In one study this alteration (designated as c.861-1G>A) was observed in a 36 year-old male with HNPCC who had a higher frequency of mutant microsatellite fragments than age-matched normal controls (Coolbaugh-Murphy MI et al. Hum. Mutat. 2010 Mar;31(3):317-24). 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 RCV000491505 SCV000690132 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing
Invitae RCV000703166 SCV000832053 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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). Disruption of this splice site has been observed in individuals affected with Lynch syndrome (PMID: 27601186, 20052760, Invitae). This variant is also known as c.861-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 218048). 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). For these reasons, this variant has been classified as Pathogenic.
Division of Medical Genetics, University of Washington RCV001257468 SCV001434271 pathogenic Lynch syndrome I 2020-01-31 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with Lynch syndrome (Coolbaugh-Murphy 2010, Lagerstedt-Robinson 2016). This variant is not present in population databases (https://gnomad.broadinstitute.org/). This variant is expected to disrupt RNA splicing and lead to an absent or disrupted protein. Loss of expression of one allele of MSH2 is an established mechanism of disease for Lynch syndrome (Mangold 2005, Thompson 2014). Thus, this variant is interpreted as pathogenic. PM2; PVS1
Mayo Clinic Laboratories, Mayo Clinic RCV000202050 SCV000257196 likely pathogenic not provided no assertion criteria provided research

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