Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000823059 | SCV000963899 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-06-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 664878). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 27435373, 31992580, 33193653; Invitae). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change affects a donor splice site in intron 13 of the PMS2 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 PMS2 are known to be pathogenic (PMID: 21376568, 24362816). |
| Ambry Genetics | RCV002442765 | SCV002732119 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-08-17 | criteria provided, single submitter | clinical testing | The c.2275+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 13 of the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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 |
| Myriad Genetics, |
RCV003453733 | SCV004187592 | likely pathogenic | Lynch syndrome 4 | 2023-09-22 | 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 | RCV003453733 | SCV004203413 | pathogenic | Lynch syndrome 4 | 2021-11-15 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV002442765 | SCV004359022 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-24 | criteria provided, single submitter | clinical testing | This variant causes a G to C nucleotide substitution at the +1 position of intron 13 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with early onset colorectal cancer whose tumor displayed loss of PMS2 expression via immunohistochemistry (PMID: 33193653). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.2275+1G>T and c.2275+1G>A, are known to be disease-causing (ClinVar variation ID: 455697, 449208). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |