Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076667 | SCV000107708 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Invitae | RCV001854338 | SCV002270566 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2020-12-23 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with suspected Lynch syndrome (PMID: 15849733). ClinVar contains an entry for this variant (Variation ID: 91163). This variant is not present in population databases (ExAC no frequency). This variant results in the deletion of part of exon 4 (c.646-3_654del) of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). |
| Ambry Genetics | RCV002362715 | SCV002659676 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-02-20 | criteria provided, single submitter | clinical testing | The c.646-3_654del12 variant spans the 5' end of coding exon 4 in the MSH2 gene. This variant results from a deletion of 12 nucleotides at positions c.646-3 to c.654, removing the highly conserved native splice acceptor sequence. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native acceptor splice 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. |