Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076660 | SCV000107695 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Ambry Genetics | RCV000220374 | SCV000278343 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-15 | criteria provided, single submitter | clinical testing | The c.645+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the MSH2 gene. This alteration has been identified in a Polish suspected-Lynch syndrome family (Kurzawski G et al, Clin. Genet. 2006 Jan; 69(1):40-7). In addition, another alteration at the same position has been identified in high-risk families and associated with aberrant splicing in vitro (Gille JJ et al. Br J Cancer. 2002 Oct 7;87(8):892-7, Thompson BA et al. Hum Mutat. 2013 Jan;34(1):200-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 pathogenic mutation. |
| Invitae | RCV001854336 | SCV002280345 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-11-15 | criteria provided, single submitter | clinical testing | Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 16451135, 22949379). ClinVar contains an entry for this variant (Variation ID: 91156). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12373605, 16451135, 16884359, 25117503, 28874130). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. For these reasons, this variant has been classified as Pathogenic. |
| Mendelics | RCV002247472 | SCV002517328 | likely pathogenic | Lynch syndrome 1 | 2022-05-04 | criteria provided, single submitter | clinical testing |