Submissions for variant NM_000535.7(PMS2):c.904-2A>G

dbSNP: rs587781339

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129110	SCV000183822	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	clinical testing	The c.904-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 9 of the PMS2 gene. This alteration has been reported in an individual whose colorectal tumor demonstrated high microsatellite instability and family history met Amsterdam criteria (Rohlin A et al. Fam Cancer, 2017 04;16:195-203). This alteration has also been reported in an individual who had right colorectal cancer at age 48, prostate cancer at age 68, and numerous polyps (Selkirk CG et al. Fam. Cancer, 2014 Dec;13:527-36). 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 presented in the literature, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206112	SCV000261727	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with clinical features consistent with Lynch syndrome (PMID: 25117502, 27696107, 28514183, 28888541). ClinVar contains an entry for this variant (Variation ID: 140880). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Counsyl	RCV000576592	SCV000677800	likely pathogenic	Lynch syndrome 4	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129110	SCV000686254	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 24763289, 25117502, 27696107, 28514183). 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 Likely Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465529	SCV002760380	likely pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492494	SCV002795199	likely pathogenic	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-11-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576592	SCV004019842	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.
Baylor Genetics	RCV000576592	SCV004203415	pathogenic	Lynch syndrome 4	2021-10-07	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV002465529	SCV005197209	likely pathogenic	not provided	2024-03-06	criteria provided, single submitter	clinical testing