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

dbSNP: rs1554300689

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629948	SCV000750904	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-23	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 525719). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). 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).
Genetics and Molecular Pathology, SA Pathology	RCV002272310	SCV002556434	likely pathogenic	Lynch syndrome 4	2019-07-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002377347	SCV002688041	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	The c.903+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 8 of the PMS2 gene. This variant was identified in an individual meeting Amsterdam criteria whose tumor demonstrated loss of PMS2 protein expression by IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002272310	SCV004171474	pathogenic	Lynch syndrome 4	2023-10-16	criteria provided, single submitter	clinical testing	The PMS2 c.903+1G>C intronic change results in a G to C substitution at the +1 position of intron 8 of the PMS2 gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or abnormal protein product. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in an individual with a brain tumor (internal data). Additionally, another variant impacting the same donor site, c.903G>T, has been reported in individuals with Lynch syndrome and CMMRD, and RNA studies for this variant have demonstrated skipping of exon 8 (PMID: 18602922, 26247049, 26318770). In summary, the c.903+1G>C variant meets criteria to be classified as pathogenic.
Myriad Genetics, Inc.	RCV002272310	SCV004187649	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.