Submissions for variant NM_000535.7(PMS2):c.2382dup (p.Gly795fs)

gnomAD frequency: 0.00001  dbSNP: rs1231406078

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574352	SCV000663534	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The c.2382dupT pathogenic mutation, located in coding exon 14 of the PMS2 gene, results from a duplication of T at nucleotide position 2382, causing a translational frameshift with a predicted alternate stop codon (p.G795Wfs*29). This alteration occurs at the 3' terminus of thePMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 68 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in multiple individuals from a family that meets Bethesda criteria for Lynch syndrome, and the tumor of at least one of these individuals was found to have absence of PMS2 via immunohistochemistry testing (Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001046563	SCV001210468	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly795Trpfs*29) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acid(s) of the PMS2 protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20587412, 31433215). ClinVar contains an entry for this variant (Variation ID: 480351). This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Trp841Glyfs*10) have been determined to be pathogenic (PMID: 10037723, 26116798, 28218421, 30764633). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451230	SCV004187708	pathogenic	Lynch syndrome 4	2023-09-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493650	SCV004243277	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017677	SCV004848376	likely pathogenic	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The p.Gly795TrpfsX29 variant in PMS2 has been reported in 1 individual with PMS2-related cancers and segregated with disease in 2 affected relatives (Sjursen 2010 PMID: 20587412). The variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 795 and leads to a premature termination codon 29 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. This truncation impacts the critical MLH1 interaction domain (amino acids 675-850) and would impair protein function (Guerrette 1998 PMID: 10037723). In addition, several loss-of-function variants occuring nearby as well as downstream of this variant have been reported in individuals with PMS2-related cancers. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary non-polyposis colorectal cancer syndrome. ACMG/AMP Criteria applied: VS1_Strong, PM1, PM2_Supporting, PS4_Supporting. Please note, this variant is in a region with high homology to the PMS2 pseudogene and should be confirmed by another orthogonal assay.