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

gnomAD frequency: 0.00001  dbSNP: rs1231406078

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574352	SCV000663534	pathogenic	Hereditary cancer-predisposing syndrome	2018-02-21	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 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). This alteration is expected to result in loss of function by premature protein truncation. As such, 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