Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076267 | SCV000107288 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
Invitae | RCV000804797 | SCV000944727 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2018-10-16 | criteria provided, single submitter | clinical testing | This sequence change affects a donor 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). Disruption of this splice site has been observed in a family affected with Lynch syndrome (PMID: 11772966). ClinVar contains an entry for this variant (Variation ID: 90768). 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 | RCV001013049 | SCV001173584 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-05-25 | criteria provided, single submitter | clinical testing | The c.1759+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 11 in the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic. |
All of Us Research Program, |
RCV000076267 | SCV004838909 | likely pathogenic | Lynch syndrome | 2024-01-08 | criteria provided, single submitter | clinical testing | The c.1759+2T>C variant of the MSH2 gene is expected to affect mRNA splicing and result in an absent or disrupted protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in MSH2 are known to be pathogenic (PMID: 15849733, 19419416). Therefore, this variant is classified as likely pathogenic. |
Human Genome Sequencing Center Clinical Lab, |
RCV000076267 | SCV005045727 | likely pathogenic | Lynch syndrome | 2023-09-22 | criteria provided, single submitter | clinical testing | The c.1759+2T>C variant of the MSH2 gene is expected to affect mRNA splicing and result in an absent or disrupted protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in MSH2 are known to be pathogenic (PMID: 15849733, 19419416). Therefore, this variant is classified as likely pathogenic. |