Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000572925 | SCV000663488 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-26 | criteria provided, single submitter | clinical testing | The c.1181delA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1181, causing a translational frameshift with a predicted alternate stop codon (p.K394Sfs*4). 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. |
| Labcorp Genetics |
RCV000798713 | SCV000938342 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-11-15 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys394Serfs*4) 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 variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 480320). For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003451227 | SCV004188631 | 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. |
| Color Diagnostics, |
RCV000572925 | SCV004359629 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-11-16 | criteria provided, single submitter | clinical testing | This variant deletes 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV001357241 | SCV001552652 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The PMS2 p.Lys394Serfs*4 variant was not identified in the literature nor was it identified in dbSNP, GeneInsight-COGR, Cosmic, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in ClinVar (classified as pathogenic by Ambry Genetics). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1181del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 394 and leads to a premature stop codon at position 397. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in PMS2-associated cancers and is the type of variant expected to cause the disorder. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |