Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000802454 | SCV000942286 | likely pathogenic | not provided | 2022-01-26 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 4 of the MSH3 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 MSH3 are known to be pathogenic (PMID: 27476653). This variant is present in population databases (rs749929790, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 647849). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Myriad Genetics, |
RCV003458531 | SCV004189012 | likely pathogenic | Familial adenomatous polyposis 4 | 2023-08-29 | 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. |
| Ambry Genetics | RCV004944174 | SCV005444632 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-10-30 | criteria provided, single submitter | clinical testing | The c.792+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the MSH3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 71 amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |