Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075326 | SCV000106319 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Invitae | RCV000797048 | SCV000936587 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-10-28 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 89852). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 15849733, 17054581; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 15 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). |
| Myriad Genetics, |
RCV003451055 | SCV004186412 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-21 | 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. 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]. |