Submissions for variant NM_000535.7(PMS2):c.2002A>G (p.Ile668Val) (rs869320619)

Minimum review status:		Collection method:
Minimum conflict level:
		ClinVar version:

Total submissions: 3

Download table as spreadsheet

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000630142	SCV000751098	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-08-25	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.
Color	RCV001179765	SCV001344501	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-21	criteria provided, single submitter	clinical testing
OMIM	RCV000172908	SCV000223890	pathogenic	Turcot syndrome	2015-05-01	no assertion criteria provided	literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.