Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075256 | SCV000106254 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Labcorp Genetics |
RCV000524243 | SCV000543640 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-04-22 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 13 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (PMID: 10200055, 24344984). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. This variant is also known as "cagACT->caaACT at splice acceptor of exon 14". ClinVar contains an entry for this variant (Variation ID: 89782). Studies have shown that disruption of this splice site results in skipping of exon 14 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.1559-2 nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12183410, 12373605, 21642682, 22322191, 22949379, 24278394). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003451034 | SCV004186516 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-20 | 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]. |
| Clinical Genetics Laboratory, |
RCV004696681 | SCV005199146 | likely pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing |