Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076822 | SCV000108309 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
| Invitae | RCV001034628 | SCV000552001 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-07-09 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg578Alafs*3) 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 (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and constitutional mismatch repair deficiency (CMMR-D) associated tumors (PMID: 17557300, 22585707). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91310). For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003452985 | SCV004187670 | pathogenic | Lynch syndrome 4 | 2023-09-20 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003478997 | SCV004222917 | pathogenic | Hereditary nonpolyposis colon cancer | 2023-11-20 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.1730dupA (p.Arg578AlafsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251352 control chromosomes. c.1730dupA has been reported in the literature as a biallelic genotype alongside another pathogenic PMS2 variant in two siblings affected with features of Constitutional Mismatch Repair Deficiency (CMMRD) (Auclair_2007 cited in Bodo_2015 and preumed overlap with Suerink_2019). The following publications have been ascertained in the context of this evaluation (PMID: 17557300, 26116798, 31204389). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on PMS2 loss of function as an established mechanism of disease and the evidence outlined above, the variant was classified as pathogenic. |