Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000535.6 | Alternative | 5156 nt | 88–2676 |
| NM_000535.4 | Alternative | 2836 nt | 88–2676 |
| NM_000535.7 | MANE Select | 5093 nt | 31–2619 |
| NM_000535.3 | Alternative | 2820 nt | 57–2645 |
| NM_000535.5 | Alternative | 2851 nt | 88–2676 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis sequence change affects an acceptor splice site in intron 3 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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 disease. Donor and acceptor splice site variants 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). 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.
"This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.73 | -1 bp |
| Donor Loss (DL) | 0.84 | -103 bp |
| Acceptor Gain (AG) | 0.0 | -24 bp |
| Donor Gain (DG) | 0.01 | 373 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong strength: Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD." The evidence for this variant shows: c.251-1G>T alters the canonical splice donor site (IVS-1) of PMS2 and is predicted to cause exon skipping leading to a frameshift and nonsense‐mediated decay. Therefore, this criterion is applied at Very Strong strength because it is a canonical splice site variant predicted to result in loss of function in PMS2.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established as Pathogenic." The evidence for this variant shows: it is a splice site variant, not a missense substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no confirmed de novo occurrence. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity > 18.7; Moderate: odds >4.3 and ≤18.7; Supporting: odds >2.08 and ≤4.3." The evidence for this variant shows: no functional assay data are available. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows: no case–control or prevalence data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-studied functional domain." The evidence for this variant shows: it is a splice site change, not in a defined functional domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting strength: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: it is not present in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Points-based evidence for variants observed in trans with a pathogenic variant in a recessive disease." The evidence for this variant shows: no data on trans configuration with another pathogenic PMS2 variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a splice site variant, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change is Pathogenic." The evidence for this variant shows: it is a splice site variant, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation where missense variants are a common mechanism of disease." The evidence for this variant shows: it is a splice site variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting strength: Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥ 0.2." The evidence for this variant shows: it is at a canonical splice site (IVS-1), not a non-canonical site. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting strength: One or more tumors with MSI-H or loss of MMR protein expression consistent with the gene." The evidence for this variant shows: no tumor or IHC data. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available for independent evaluation." The evidence for this variant shows: ClinVar reports two Likely Pathogenic and one Pathogenic submissions without primary evidence. Therefore, this criterion is applied at Supporting strength because a reputable source classifies the variant as pathogenic without evaluation data.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone strength: gnomAD v4 allele frequency ≥ 0.28%." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong strength: gnomAD v4 allele frequency 0.01–0.1%." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong strength: Co-occurrence in trans with a known pathogenic variant without CMMRD." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong strength: Calibrated functional assays showing no abnormality; Supporting: odds >0.05 & ≤0.48." The evidence for this variant shows: no functional assays demonstrating normal function. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants are known to cause disease." The evidence for this variant shows: it is a splice site variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene, or observed in cis with a pathogenic variant." The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known function." The evidence for this variant shows: it is a splice site variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting strength: SpliceAI predicts no splicing impact with delta score ≤ 0.1 for intronic/synonymous variants." The evidence for this variant shows: SpliceAI delta = 0.84, indicating impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Strong: Multiple tumors with MSS/no loss of MMR protein expression inconsistent with gene; Supporting: fewer tumors or single BRAF V600E/MLH1 methylation event." The evidence for this variant shows: no tumor profiling data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence is unavailable." The evidence for this variant shows: no benign assertions. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting strength: Synonymous or intronic variant at or beyond −21/+7." The evidence for this variant shows: position −1 is within the critical splice region. Therefore, this criterion is not applied.