Submissions for variant NM_000535.7(PMS2):c.903+1G>T

dbSNP: rs1554300689

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000584297	SCV000691122	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-11-23	criteria provided, single submitter	clinical testing
Invitae	RCV001378093	SCV001575582	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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 colorectal cancer (PMID: 30608896). ClinVar contains an entry for this variant (Variation ID: 492303). 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.
Ambry Genetics	RCV000584297	SCV002686335	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-07-17	criteria provided, single submitter	clinical testing	The c.903+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 8 of the PMS2 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of PMS2 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. 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 likely pathogenic.
Myriad Genetics, Inc.	RCV003451312	SCV004187645	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.