Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075683 | SCV000106687 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Invitae | RCV001235385 | SCV001408067 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-10-21 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 4 of the MLH1 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 MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (Invitae). ClinVar contains an entry for this variant (Variation ID: 90195). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 8971183, 10375096, 26248088, 28944238; Invitae). It has also been observed to segregate with disease in related individuals. |
| Myriad Genetics, |
RCV003451143 | SCV004187313 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-13 | criteria provided, single submitter | clinical testing | This variant is considered likely 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. |