Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
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 Nonsense/frameshift variant introducing Premature Termination Codon (PTC) a ≤ codon 891 in MSH2." The evidence for this variant shows: c.802dupT (p.Ser268Phefs*16) introduces a frameshift and premature stop at codon ~284, well ≤891. Therefore, this criterion is applied at Very Strong strength because the variant is a null (frameshift) variant in a gene where loss-of-function is a known mechanism of disease.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies only to missense substitutions encoding the same amino acid change as a known pathogenic variant. The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence. The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, PS3 (Strong) is: "MMR function defect following functional assay flowchart." The evidence for this variant shows: in vitro studies demonstrate that p.Ser268Phefs*16 truncates the protein, abolishing MutS domain function and mismatch repair activity. Therefore, this criterion is applied at Strong strength because well-established functional studies demonstrate loss of function.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals over controls (case–control or family segregation data). The evidence for this variant shows: no case–control or statistical association data provided. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 applies to variants located in mutational hot spots or critical functional domains without benign variation. The evidence for this variant shows: it is a frameshift outside of a defined domain-specific hot spot rule. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 (Supporting) is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: not present in population databases including gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies to recessive disorders with detected trans configuration with another pathogenic variant. The evidence for this variant shows: no data on trans configuration or recessive inheritance. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length–altering variants other than truncating variants already captured by PVS1. The evidence for this variant shows: it is a truncating frameshift, which is covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies to novel missense changes at a residue with a different pathogenic missense change. The evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation of parentage. The evidence for this variant shows: no de novo evidence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 requires co-segregation with disease in multiple affected family members. The evidence for this variant shows: no segregation data provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. The evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies to missense variants or splicing predictions with significant in silico support. The evidence for this variant shows: it is a truncating frameshift, and in silico splicing scores are low. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 requires a highly specific phenotype or tumor characteristics. The evidence for this variant shows: no tumor or phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 (reputable source) is deprecated and should not be used. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 requires allele frequency ≥0.1% in gnomAD. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 requires allele frequency between 0.01% and 0.1%. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies to co-occurrence in trans with another pathogenic variant in a patient without CMMRD. The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 applies to well-established functional studies showing no damaging effect. The evidence for this variant shows: functional studies demonstrate damage. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 requires lack of segregation. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where truncating variants are known to cause disease. The evidence for this variant shows: it is truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies to observed in trans with a pathogenic variant for a dominant disorder. The evidence for this variant shows: no trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 applies to intronic/synonymous variants with no splicing impact predicted (delta ≤0.1). The evidence for this variant shows: it is a coding frameshift. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies to variants found in a case with an alternate molecular basis for disease. The evidence for this variant shows: no such context. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies to a reputable source reporting a variant as benign without evidence. The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants with no splicing effect. The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.