Submissions for variant NM_000535.7(PMS2):c.862_863del (p.Gln288fs)

dbSNP: rs63750246

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076895	SCV000108391	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000165221	SCV000215935	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	The c.862_863delCA pathogenic mutation, located in coding exon 8 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 862 to 863, causing a translational frameshift with a predicted alternate stop codon (p.Q288Vfs*10). This alteration has been reported in an individual with colon cancer at age 54 with absent PMS2 IHC expression (Clendenning M, Hum. Mutat. 2006 May; 27(5):490-5.) In addition, this alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000627706	SCV000218667	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln288Valfs*10) 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 Lynch syndrome (PMID: 16619239, 18602922). ClinVar contains an entry for this variant (Variation ID: 91376). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000411556	SCV000488646	pathogenic	Lynch syndrome 4	2016-05-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165221	SCV000686248	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 8 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. This variant has been reported in an individual affected with colorectal cancer, whose tumor demonstrated microsatellite instability and loss of PMS2 protein via immunohistochemistry analysis (PMID: 16619239). 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.
GeneDx	RCV000657185	SCV000778907	pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 16619239, 18602922, 28514183); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 30787465, 28514183, 28888541, 27435373, 18602922, 16619239, 36644715)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255504	SCV001431935	pathogenic	Hereditary nonpolyposis colon cancer	2020-08-07	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.862_863delCA (p.Gln288ValfsX10) 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. The variant was absent in 251446 control chromosomes (gnomAD). c.862_863delCA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Clendenning_2006, Espenschied_2017, Senter_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657185	SCV002046363	pathogenic	not provided	2021-05-12	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of PMS2 protein synthesis. It has been reported in an individual with colorectal cancer in the published literature (PMID: 18602922 (2008) and 16619239 (2006)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Therefore, the variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000411556	SCV004019952	pathogenic	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
PreventionGenetics, part of Exact Sciences	RCV003415836	SCV004109151	pathogenic	PMS2-related condition	2024-02-01	criteria provided, single submitter	clinical testing	The PMS2 c.862_863delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln288Valfs*10). This variant was reported in an individual with Lynch syndrome (Clendenning et al 2006. PubMed ID: 16619239). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in PMS2 are expected to be pathogenic. This variant is listed in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/91376/). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000411556	SCV004207796	pathogenic	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing