Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV001355016 | SCV001549771 | pathogenic | Endometrial carcinoma | no assertion criteria provided | clinical testing | The PMS2 c.989-?_1144+?del variant (chr:7 g.6029431_6029586del GRCh37) results in a deletion of exon 10, the precise breakpoints of this deletion were not determined, nor were the effects of this variant on the resulting mRNA or protein product determined. The PMS2 c.989-?_1144+?del variant was identified in 10 of 2736 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer, Lynch syndrome, and endometrial cancer (Jóri 2015, Senter 2008, Van der Klift 2005, van der Klift 2010, Hendriks 2006, Overbeek 2007, Tomsic 2013). The variant was also identified in the following databases: ClinVar (1x, as pathogenic by Invitae), Clinvitae (1x, as pathogenic by Invitae), Insight Colon Cancer Gene Variant Database (10x, as class 5 pathogenic with break points identified as: c.898-296_1144+706del), Mismatch Repair Genes Variant Database (3x), Insight Hereditary Tumors Database (reported 8x). The variant was not identified in dbSNP, Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.989-?_1144+?del variant has been identified as pathogenic in multiple studies utilizing techniques such as RT-PCR, long range PCR, Southern blot, MLPA and RNA base long range PCR (Jóri 2015, Senter 2008, Van der Klift 2005, van der Klift 2010, Hendriks 2006, Overbeek 2007, Tomsic 2013). The break points for this variant has been identified by multiple studies as (c.989-296_144+706del) and confirmed as identical in all subjects (van der Klift 2005, Overbeek 2007, Tomsic 2013). Genotyping and haplotype analyses found evidence of a shared haplotypes present in all unrelated subjects and 2 of 80 control cases, suggesting that this is a founder mutation. All subjects were Caucasian with unknown ancestral origin (Tomsic 2013). This variant is an in-frame deletion resulting in the removal of PMS2 exon 10. This deletion is predicted to result in altered protein product and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |