Submissions for variant NM_000535.7(PMS2):c.247_250dup (p.Thr84fs)

dbSNP: rs1554304940

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479446	SCV000569466	pathogenic	not provided	2016-06-06	criteria provided, single submitter	clinical testing	This duplication of 4 nucleotides in PMS2 is denoted c.247_250dupTTAA at the cDNA level and p.Thr84IlefsX9 (T84IfsX9) at the protein level. The normal sequence, with the bases that are duplicated in braces, is AGGC[TTAA]GTAA. The duplication causes a frameshift which changes a Threonine to an Isoleucine at codon 84, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PMS2 c.247_250dupTTAA has been identified in individuals with Lynch syndrome-associated cancers, with tumor testing in at least one of these individuals showing microsatellite instability (MSI-H) and loss of PMS2 protein expression (Dudley 2015, Suerink 2015). We consider this variant to be pathogenic.
Revvity Omics, Revvity	RCV000479446	SCV002019441	pathogenic	not provided	2021-04-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446929	SCV002733927	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-25	criteria provided, single submitter	clinical testing	The c.247_250dupTTAA pathogenic mutation, located in coding exon 3 of the PMS2 gene, results from a duplication of TTAA at nucleotide position 247, causing a translational frameshift with a predicted alternate stop codon (p.T84Ifs*9). This mutation has been reported in multiple individuals with a personal history of endometrial cancer, with at least one patient's tumor demonstrating microsatellite instability (MSI-H) and loss of PMS2 expression on immunohistochemistry (IHC) (Dudley B et al. Am. J. Surg. Pathol., 2015 Aug;39:1114-20; van der Klift HM et al. Hum. Mutat., 2016 11;37:1162-1179; Roberts ME et al. Genet. Med., 2018 10;20:1167-1174). This mutation was reported 1/130 European families with PMS2 mutations meeting either Bethesda criteria or "MSI-testing-indicated-by-a-pathologist" criteria (Suerink M et al. Genet. Med., 2016 Apr;18:405-9). This mutation has also been reported in the compound heterozygous state with another PMS2 mutation in a patient with constitutional mismatch repair deficiency (CMMRD) (Leenders EKSM et al. Eur. J. Hum. Genet., 2018 10;26:1417-1423). In addition to the clinical data presented in the literature, 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.
Invitae	RCV002525844	SCV003439917	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 420580). This premature translational stop signal has been observed in individual(s) with Lynch Syndrome (PMID: 25871621). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr84Ilefs*9) 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).
Myriad Genetics, Inc.	RCV003449209	SCV004188690	pathogenic	Lynch syndrome 4	2023-09-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV004003328	SCV004814296	pathogenic	Lynch syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with PMS2-related cancer (PMID: 25871621, 33693762, 34873870). It has also been reported in the compound heterozygous state with another PMS2 variant in a child with constitutional mismatch repair deficiency (PMID: 29904176, 34964038). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).