Submissions for variant NM_000535.7(PMS2):c.988+1G>C

dbSNP: rs757110564

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002013192	SCV002294683	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-04-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics	RCV002386875	SCV002693240	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	clinical testing	The c.988+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 9 of the PMS2 gene. This alteration has been identified in a proband whose Lynch syndrome associated tumor demonstrated loss of PMS2 expression on immunohistochemistry (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal 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.
Myriad Genetics, Inc.	RCV003453948	SCV004187603	likely pathogenic	Lynch syndrome 4	2023-09-19	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.