Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000630142 | SCV000751098 | likely pathogenic | Hereditary nonpolyposis colon cancer | 2017-10-24 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine with valine at codon 668 of the PMS2 protein (p.Ile668Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with constitutional mismatch repair deficiency (CMMRD) in several families, and has been shown to be a founder mutation in affected individuals with Inuit ancestry (PMID: 25691505). ClinVar contains an entry for this variant (Variation ID: 192316). Experimental studies in patient derived lymphocytes demonstrated that this missense change generates an alternative splice site at the exon 11–12 junction, resulting in aberrant RNA splicing and the production of a dominant transcript with a 5 base pair deletion that is predicted to lead to nonsense-mediated decay (PMID: 25691505). Further analysis of patient derived samples indicate that a full-length transcript is also produced at low levels resulting in residual expression that may underlie the attenuated CMMRD phenotype that has been reported to be associated with homozygous status of this variant (PMID: 25691505). 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. |
| OMIM | RCV000172908 | SCV000223890 | pathogenic | Turcot syndrome | 2015-05-01 | no assertion criteria provided | literature only |