Submissions for variant NM_000535.7(PMS2):c.537+1del

dbSNP: rs1064793868

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485795	SCV000567235	pathogenic	not provided	2015-07-08	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted PMS2 c.537+1delG or IVS5+1delG and consists of a single nucleotide deletion at the +1 position of intron 5 of the PMS2 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-medicated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Based on the current evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223326	SCV001395468	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu180Serfs*21) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. 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). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is also known as c.537+1del. ClinVar contains an entry for this variant (Variation ID: 419435). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000758169	SCV002646454	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	clinical testing	The c.537+1delG intronic pathogenic mutation, located in intron 5 of the PMS2 gene, results from a deletion of one nucleotide within intron 5 of the PMS2 gene. This variant has been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or 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 and will result in the creation or strengthening of a novel 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.
Fulgent Genetics, Fulgent Genetics	RCV002506164	SCV002813821	likely pathogenic	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-11-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003449191	SCV004187642	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.
Baylor Genetics	RCV003449191	SCV004205406	likely pathogenic	Lynch syndrome 4	2023-10-06	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004556788	SCV005045767	likely pathogenic	Lynch syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The c.537+1del variant in the PMS2 gene is located at the canonical splice site of intron 5 and is predicted to inflict donor loss (SpliceAI delta score: 0.99), resulting in alternative splicing and disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar (ID: 419435). The variant is absent in the general population database (gnomAD). Therefore, the c.537+1del variant of PMS2 has been classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000485795	SCV005439157	likely pathogenic	not provided	2023-09-13	criteria provided, single submitter	clinical testing	PM2_moderate, PVS1
True Health Diagnostics	RCV000758169	SCV000886701	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-03	no assertion criteria provided	clinical testing