Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000689815 | SCV000817482 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2018-06-12 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 3 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). 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. |
| Ambry Genetics | RCV002424609 | SCV002742521 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-20 | criteria provided, single submitter | clinical testing | The c.251-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 4 of the PMS2 gene. Another alteration impacting the same acceptor site (c.251-2A>T) has been detected in individuals whose Lynch syndrome-associated tumors demonstrated isolated loss of PMS2 expression by immunohistochemistry (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV003453438 | SCV004187629 | likely pathogenic | Lynch syndrome 4 | 2023-09-18 | 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. |