Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002365051 | SCV002663002 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-02-01 | criteria provided, single submitter | clinical testing | The c.706-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 7 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 acceptor site and may result in the creation or strengthening of a novel 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. As such, this alteration is classified as likely pathogenic. |
Revvity Omics, |
RCV003491098 | SCV004238594 | likely pathogenic | not provided | 2023-03-15 | criteria provided, single submitter | clinical testing | |
Invitae | RCV003594236 | SCV004271396 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-04-06 | criteria provided, single submitter | clinical testing | 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. 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: 1756960). Disruption of this splice site has been observed in individual(s) with PMS2-related conditions (PMID: 31948886; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects an acceptor splice site in intron 6 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). |
Laboratory for Molecular Medicine, |
RCV004017928 | SCV004847961 | likely pathogenic | Lynch syndrome | 2018-04-02 | criteria provided, single submitter | clinical testing | The c.706-G>T variant in PMS2 has not been previously reported in individuals with Lynch syndrome or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, although additional studies are required to fully establish its clinical significance, the c.706-G>T variant is likely pathogenic. ACMG criteria applied: PVS1; PM2. |