Submissions for variant NM_000535.7(PMS2):c.164-1G>C

dbSNP: rs763308607

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165585	SCV000216319	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	clinical testing	The c.164-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 3 of the PMS2 gene. This alteration is detected in several individuals whose colorectal or endometrial tumors demonstrated loss of PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). This alteration is also detected in an individual diagnosed with colorectal cancer at 45, and an individual diagnosed with endometrial cancer at 55 with demonstrated high microsatellite instability; however, the IHC results for the endometrial cancer demonstrated loss of MSH6 expression and were non-interpretable for PMS2 (Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Wang Q et al. J Med Genet, 2020 07;57:487-499). 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; however, direct evidence is insufficient at this time (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.
GeneDx	RCV000484767	SCV000572224	likely pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to disrupt splicing in a gene for which loss of function is a known mechanism of disease; Published RNA studies suggest this variant results in use of a cryptic splice site and an aberrant transcript which is predicted to lead to a frameshift (Ryu et al., 2020); Identified in patients tested at GeneDx and in published literature with Lynch syndrome-related cancer and tumors demonstrating microsatellite instability and/or loss of PMS2 staining; some individuals also harbored a second PMS2 pathogenic variant in cis (Goodenberger et al., 2016; Ryu et al., 2020; Wang et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 11574484, 34172528, 32761968, 31802016, 31992580)
Counsyl	RCV000576564	SCV000677817	likely pathogenic	Lynch syndrome 4	2017-03-17	criteria provided, single submitter	clinical testing
Invitae	RCV000792721	SCV000932033	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 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 present in population databases (rs763308607, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25856668, 31992580). ClinVar contains an entry for this variant (Variation ID: 186061). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000484767	SCV002018877	likely pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000576564	SCV003835158	pathogenic	Lynch syndrome 4	2022-03-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576564	SCV004019853	likely pathogenic	Lynch syndrome 4	2023-04-04	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.
Color Diagnostics, LLC DBA Color Health	RCV000165585	SCV004359711	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-07	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 2 of the PMS2 gene. Functional RNA studies have shown that this variant causes a partial deletion of exon 3, resulting in premature truncation (PMID: 32761968). This variant has been reported in individuals affected with Lynch syndrome (PMID: 25856668, 31992580; ClinVar SCV000216319.6, SCV000572224.5). This variant has been identified in 1/248116 chromosomes 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.