Submissions for variant NM_000535.7(PMS2):c.2445+1G>T

dbSNP: rs876661113

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000219334	SCV000279559	pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (van der Klift et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20205264, 25525159, 19132747, 27435373, 26110232, 23012243, 25512458, 24362816, 28702897, 26247049, 30787465, 33087929)
Invitae	RCV000228982	SCV000285122	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the 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. Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 19132747, 20205264, 23012243, 25512458, 26110232). ClinVar contains an entry for this variant (Variation ID: 234604). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (PMID: 26247049; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. 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, 16338176, 20533529, 26116798, 28218421). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507182	SCV000604887	pathogenic	not specified	2016-08-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575263	SCV000670739	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	clinical testing	The c.2445+1G>T pathogenic mutation results from a G to T substitution one nucleotide after coding exon 14 of the PMS2 gene. This alteration has been reported in two HNPCC/Lynch syndrome patients: one with an MSI-H colorectal cancer diagnosed at 31 years of age and the other with a transverse colon cancer diagnosed at age 34 which demonstrated isolated absence of PMS2 on immunohistochemistry (IHC) (Niessen R et al. Genes Chromosomes Cancer. 2009 Apr;48(4):322-9; Vaughn C et al. Hum. Mutat. 2010 May;31(5):588-93). RNA studies for c.2445+1G>T demonstrated the presence of an aberrant transcript leading to premature protein truncation; however, levels of full-length/normal transcript were not assessed (van der Klift H et al. Mol. Genet. Genomic Med. 2015 Jul;3(4):327-45). This position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000219334	SCV001247255	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193818	SCV001362952	pathogenic	Hereditary nonpolyposis colon cancer	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2445+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports the variant to result in aberrant transcripts as assessed through minigene assays in HEK293 and HeLa cell lines and also, following analysis of patient RNA where retention of 85bp of flanking intronic sequence was observed (van der Klift_2015). The variant was absent in 194842 control chromosomes. c.2445+1G>T, has been reported in the literature in individuals affected with colorectal cancer (Niessen_2009, Vaughn_2010, ten Broeke_2015) or gynecological cancer (Delahunty_2022). The following publications have been ascertained in the context of this evaluation (PMID: 19132747, 26110232, 20205264, 25512458, 26247049, 35263119). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; seven submitters classified the variant as pathogenic and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219334	SCV001470054	pathogenic	not provided	2020-08-05	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
MGZ Medical Genetics Center	RCV002288907	SCV002581881	likely pathogenic	Lynch syndrome 4	2022-08-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494606	SCV002797927	pathogenic	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-04-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288907	SCV004187576	likely pathogenic	Lynch syndrome 4	2023-09-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics	RCV002288907	SCV004207783	pathogenic	Lynch syndrome 4	2023-07-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000219334	SCV000691958	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358436	SCV001554166	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 c.2445+1G>T variant was identified in 3 of 1152 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome or colorectal cancer (Niessen 2009, Suerink 2015, ten Broeke 2015). The variant was also identified in dbSNP (ID: rs876661113) as "With Likely pathogenic, Pathogenic allele" and ClinVar (classified as pathogenic by Invitae, ARUP, Ambry Genetics and GeneDx). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.2445+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Further, RNA-based mutation scanning found this variant produced two aberrant splice products in cultured lymphocyte RNA (van der Klift 2015). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000219334	SCV001742120	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000219334	SCV001952646	pathogenic	not provided		no assertion criteria provided	clinical testing