Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076519 | SCV000107549 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| University of Washington Department of Laboratory Medicine, |
RCV000076519 | SCV000887429 | pathogenic | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MSH2 NM_000251.2:c.2634+1G>T has a 99.96% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. |
| Ambry Genetics | RCV001016179 | SCV001177101 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-31 | criteria provided, single submitter | clinical testing | The c.2634+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the MSH2 gene. This alteration has been identified in multiple colorectal cancer/Lynch syndrome cohorts (Yuen ST et al. Oncogene, 2002 Oct;21:7585-92; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Sjursen W et al. J Med Genet, 2010 Sep;47:579-85; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). In addition, this variant has been identified as somatic in conjunction with MSH2 copy neutral loss of heterozygosity (CN-LOH) in a tumor that demonstrated high microsatellite instability, loss of MSH2 expression and focal staining of MSH6 by immunohistochemistry (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the published data, 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 | RCV001386003 | SCV001586074 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-10-23 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 15 of the MSH2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12386821, 15849733, 21642682). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS15+IG>T. ClinVar contains an entry for this variant (Variation ID: 91017). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003452924 | SCV004188075 | pathogenic | Lynch syndrome 1 | 2023-08-09 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 3658675]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. |
| Constitutional Genetics Lab, |
RCV001250026 | SCV001423951 | pathogenic | Lynch-like syndrome | 2019-07-01 | no assertion criteria provided | clinical testing |