Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000564600 | SCV000674231 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-13 | criteria provided, single submitter | clinical testing | The c.803+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the PMS2 gene. This alteration was identified as germline in conjunction with a pathogenic PMS2 somatic mutation in an individual with colorectal cancer that displayed high microsatellite instability (MSI-H) and loss of PMS2 on immunohistochemistry (IHC), but no MLH1 promoter hypermethylation was detected (Ambry internal data). Furthermore, in this family, c.803+5G>A segregated with disease in a sibling diagnosed with endometrial cancer that demonstrated loss of PMS2 on IHC (Ambry internal data). This alteration was also identified in two French patients, one with endometrial cancer that was MSI-H and the other with colorectal cancer that was MSI-H and also demonstrated loss of PMS2 on IHC (Wang Q et al. J Med Genet, 2020 07;57:487-499). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV000630211 | SCV000751167 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-09-27 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with PMS2-related conditions (PMID: 31992580; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 486041). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (Invitae). 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. |