Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075813 | SCV000106827 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Ambry Genetics | RCV002362712 | SCV002662439 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-08-22 | criteria provided, single submitter | clinical testing | The c.678-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 9 of the MLH1 gene. This mutation has been reported in a 27 year old individual diagnosed with colorectal cancer (CRC) whose tumor showed high microsatellite instability (MSI-H) and absent MLH1 and PMS2 staining on immunohistochemistry; this family met Amsterdam criteria (Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98). This mutation was also reported in a Korean individual diagnosed at age 13 with a MSI-H CRC (Ahn DH et al. Korean J Pediatr. 2016 Jan;59:40-2). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation. |
| Myriad Genetics, |
RCV003452760 | SCV004185650 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-17 | 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. |
| Invitae | RCV003593888 | SCV004293453 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-08-28 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 8 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). Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: 16237223, 16616355, 26893603). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS8-1G>C. ClinVar contains an entry for this variant (Variation ID: 90322). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. |