Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001015524 | SCV001176367 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-12-21 | criteria provided, single submitter | clinical testing | The c.2435+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 17 in the MSH3 gene. Alterations affecting canonical splice sites in MSH3 have been described in 2 polyposis families who were identified to have biallelic MSH3 alterations (Adam R et al. Am J Hum Genet. 2016 Aug 4;99(2):337-51). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic. |
| Invitae | RCV001378551 | SCV001576139 | likely pathogenic | not provided | 2023-11-25 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 17 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, 37402566). This variant is not present in population databases (gnomAD no frequency). 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: 821271). 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, |
RCV003458589 | SCV004189013 | likely pathogenic | Familial adenomatous polyposis 4 | 2023-08-30 | 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. |