Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000630128 | SCV000751084 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-10-28 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 4 of the MSH6 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 MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 22306203; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 525807). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002325200 | SCV002609724 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-29 | criteria provided, single submitter | clinical testing | The c.3173-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 5 in the MSH6 gene. This variant was identified in a proband diagnosed with endometrioid adenocarcinoma at age 62 that demonstrated high microsatellite instability and loss of MSH6 protein expression by immunohistochemistry (Leenen CH et al. Gynecol Oncol, 2012 May;125:414-20). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Myriad Genetics, |
RCV003451501 | SCV004185543 | likely pathogenic | Lynch syndrome 5 | 2023-08-22 | 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. |
| Baylor Genetics | RCV003459499 | SCV004195814 | pathogenic | Endometrial carcinoma | 2023-04-26 | criteria provided, single submitter | clinical testing |