ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.706-1G>T

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Total submissions: 4
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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, Revvity 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, Mass General Brigham Personalized 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.

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