Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000535.7(PMS2):c.1144+2T>G variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.060254924 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-5989798-A-C is Pathogenic according to our data. Variant chr7-5989798-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2584290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (Invitae). This sequence change affects a donor splice site in intron 10 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. 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: 30521064). Other variant(s) that result in the loss of exon 10 have been determined to be pathogenic (PMID: 16472587, 18602922, 22577899, 23837913, 26318770). This suggests that this variant may also be clinically significant and likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.1144+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 10 in the PMS2 gene. 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Lynch syndrome 4 Pathogenic:1
Jun 14, 2023
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -