Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The MSH2 S268Ffs*16 variant is a truncating mutation that leads to the loss of normal mismatch repair function. This disruption occurs due to the partial or complete loss of the MutS domain, which is essential for the protein's function. Consequently, this variant is likely to have a damaging effect on the mismatch repair pathway.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.04 | 1 bp |
| Donor Loss (DL) | 0.0 | 143 bp |
| Acceptor Gain (AG) | 0.06 | 0 bp |
| Donor Gain (DG) | 0.0 | -246 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2." The evidence for this variant shows: c.802dup causes a frameshift resulting in a PTC at codon ~283, well upstream of codon 891 and not in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a truncating variant in a gene where loss-of-function is a known mechanism of disease.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic." The evidence for this variant shows: c.802dup is a frameshift, 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 data on de novo occurrence or parental testing. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Strong Calibrated functional assays with functional odds for Pathogenicity > 18.7 OR MMR function defect following functional assay flowchart*." The evidence for this variant shows: in vitro and in vivo studies demonstrate that the S268Ffs*16 frameshift abolishes MSH2 mismatch repair function. Therefore, this criterion is applied at Strong strength because the variant results in an MMR function defect following the functional assay flowchart.
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 cohort 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 and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: no specific hot spot or domain criterion beyond loss-of-function is provided. 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 absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is not observed in population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: MSH2-associated Lynch syndrome is autosomal dominant and no trans data are available. 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 deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a frameshift introducing a premature stop codon, already captured by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: it is a frameshift, not a missense substitution. 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 and 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 family 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 a low rate of benign missense variation where missense is a common disease mechanism." The evidence for this variant shows: it is a truncating variant, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: SpliceAI max delta score 0.06 (<0.2) and no supporting in silico pathogenic predictions. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting Strength: 1 CRC/Endometrial MSI-H tumor and/or loss of MMR protein expression consistent with variant location." The evidence for this variant shows: no tumor phenotype or MSI-H 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 to the laboratory." The evidence for this variant shows: ClinVar records the variant as Pathogenic from one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable database reports it as pathogenic without primary evidence.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: GnomAD v4 Grpmax filtering allele frequency ≥ 0.001." The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001." The evidence for this variant shows: it is absent from gnomAD. 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 in LS cancers without evidence of CMMRD." The evidence for this variant shows: no data on co-occurrence. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Strong functional studies show no damaging effect, or synonymous/intronic with no mRNA aberration." The evidence for this variant shows: functional studies demonstrate damaging effect. 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 cause disease." The evidence for this variant shows: it is a truncating 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 in a dominant disorder." The evidence for this variant shows: no trans observations. 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." The evidence for this variant shows: it is a frameshift insertion, not an in-frame event in a repeat region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Computational evidence (e.g., SpliceAI ≤ 0.1 or HCI priors < 0.11) supports no impact on gene function." The evidence for this variant shows: SpliceAI delta score is 0.06, below threshold for splicing impact. Therefore, this criterion is applied at Supporting strength because computational tools predict no splicing effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular cause reported. 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 without available evidence." The evidence for this variant shows: no benign database report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant at or beyond -21/+7 with no splicing impact." The evidence for this variant shows: it is not a synonymous variant. Therefore, this criterion is not applied.