Submissions for variant NM_000535.7(PMS2):c.354-2A>G

dbSNP: rs786202098

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164744	SCV000215416	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	clinical testing	The c.354-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 5 in the PMS2 gene. This alteration has been identified in a family that met Amsterdam I criteria for Lynch syndrome and in multiple, unrelated patients with colorectal cancers exhibiting high microsatellite instability and/or isolated loss of PMS2 on immunohistochemistry (IHC) (Rosty C et al. BMJ Open. 2016 Feb;6(2):e010293; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae	RCV000552914	SCV000625644	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with colon cancer (PMID: 26895986; Invitae). ClinVar contains an entry for this variant (Variation ID: 185340). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759205	SCV000888416	pathogenic	not provided	2023-08-03	criteria provided, single submitter	clinical testing	The PMS2 c.354-2A>G variant disrupts a canonical splice-acceptor site and interferes with normal PMS2 mRNA splicing, resulting in the loss of a functional protein. In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 33259954 (2021), 26895986 (2016), 25856668 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Sema4, Sema4	RCV000164744	SCV002530334	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-02	criteria provided, single submitter	curation
GeneDx	RCV000759205	SCV002757494	likely pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with colorectal cancer demonstrating loss of PMS2 on immunohistochemistry (Rosty 2016); This variant is associated with the following publications: (PMID: 26895986)
Myriad Genetics, Inc.	RCV003454400	SCV004187589	likely pathogenic	Lynch syndrome 4	2023-09-18	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	RCV003454400	SCV004207779	pathogenic	Lynch syndrome 4	2023-07-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995362	SCV004814294	pathogenic	Lynch syndrome	2023-11-08	criteria provided, single submitter	clinical testing	The c.354-2A>G variant in the PMS2 gene is located at the canonical splice site of intron 4 and is predicted to inflict acceptor loss (SpliceAI delta score: 0.99), resulting in alternative splicing and disrupted protein product. The variant has been reported in 3 individuals with colorectal cancer (PMID: 25856668). Experimental MMR activity assay from the cell line derived patient cells showed the variant has a negative functional impact (29% MMR activity) (PMID: 30608896). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar (ID: 185340). The variant is absent in the general population database (gnomAD). Therefore, the c.354-2A>G variant of PMS2 has been classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000759205	SCV001553634	uncertain significance	not provided		no assertion criteria provided	clinical testing