Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076802 | SCV000108284 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
| Invitae | RCV002228025 | SCV000552077 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2020-11-10 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Thr408Leufs*40) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (ExAC no frequency). 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 create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency (PMID: 10763829). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 9235). |
| Ambry Genetics | RCV003298029 | SCV004005571 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-20 | criteria provided, single submitter | clinical testing | The c.1221delG pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1221, causing a translational frameshift with a predicted alternate stop codon (p.T408Lfs*40). This variant has been confirmed in trans with a PMS2 pathogenic variant in an individual diagnosed with Turcot's syndrome (De Rosa M et al. Oncogene, 2000 Mar;19:1719-23). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV000009816 | SCV000030037 | pathogenic | Mismatch repair cancer syndrome 4 | 2000-03-23 | no assertion criteria provided | literature only |