Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001025972 | SCV001188264 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-09-30 | criteria provided, single submitter | clinical testing | The c.705+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the PMS2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of PMS2 expression by immunohistochemistry (Ambry internal data).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Color Diagnostics, |
RCV001025972 | SCV001736400 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-12-21 | criteria provided, single submitter | clinical testing | This variant causes a G to A nucleotide substitution at the +1 position of intron 6 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. However, two other variants at this splice site, c.702+1G>T and c.705+2T>C, have been observed in an individual affected with PMS2-deficient Lynch syndrome-associated cancer (PMID: 16619239, 18602922) and an individual suspected of constitutional mismatch repair deficiency syndrome (PMID: 23629955), respectively. An RNA study also has shown that c.705+2T>C produced aberrant mRNA transcripts that have in-frame deletions in the ATPase domain (PMID: 23629955). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Myriad Genetics, |
RCV003455134 | SCV004187620 | likely pathogenic | Lynch syndrome 4 | 2023-08-03 | 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. |
| Invitae | RCV003758989 | SCV004452166 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-04-05 | 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. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 23629955). ClinVar contains an entry for this variant (Variation ID: 826800). Disruption of this splice site has been observed in individual(s) with colorectal cancer and/or PMS2-related conditions (PMID: 16619239, 23629955; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor 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). |