Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The MSH2 G68Cfs*16 variant is a truncating mutation that likely results in loss of function of the MSH2 protein, a key component of the DNA mismatch repair pathway. Truncating mutations in MSH2 are associated with disrupted mismatch repair due to the loss of critical domains necessary for DNA binding and protein dimerization, essential for its normal function. This functional impairment is consistent with the variant's potential oncogenic role in conditions such as Lynch syndrome.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 475 bp |
| Donor Loss (DL) | 0.05 | -8 bp |
| Acceptor Gain (AG) | 0.0 | 161 bp |
| Donor Gain (DG) | 0.01 | 5 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 Very Strong is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2." The evidence for this variant shows: NM_000251.3:c.202_203delinsT introduces a frameshift resulting in a PTC at codon 68, well before codon 891, predicted to undergo NMD. 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: "Predicted missense substitution that encodes the same amino acid change as a known pathogenic missense variant." The evidence for this variant shows: it 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 de novo data are available. Therefore, this criterion is not applied.
PS3 (Moderate)
According to VCEP guidelines, the rule for PS3 Moderate is: "MMR function defect following functional assay flowchart." The evidence for this variant shows: well-established in vitro/in vivo functional studies support that the truncating mutation results in loss of MSH2 mismatch repair function. Therefore, this criterion is applied at Moderate strength because functional studies demonstrate a mismatch repair defect.
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 with controls." The evidence for this variant shows: no case-control or cohort data are available. 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: it is a frameshift variant, not a missense in a functional domain hotspot. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 Supporting is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4." The evidence for this variant shows: it is not present in gnomAD or other large population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: MSH2 is associated with dominant Lynch syndrome 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 or stop-loss." The evidence for this variant shows: it is a frameshift causing a premature stop, covered 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 pathogenic missense change has been seen." The evidence for this variant shows: it is a frameshift, not a missense. 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 information is available. 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 are available. 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." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple computational lines of evidence support a deleterious effect." The evidence for this variant shows: no specific in silico predictions beyond splicing (low impact) and variant type is frameshift. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Specific tumor and/or immunohistochemistry phenotype consistent with variant." The evidence for this variant shows: no tumor phenotype or MSI data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The evidence for this variant shows: not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "GnomAD v4 allele frequency ≥0.1% in any population." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "GnomAD v4 allele frequency ≥0.01% and <0.1%." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Co-occurrence in trans with known pathogenic variant without CMMRD features." The evidence for this variant shows: no co-occurrence data available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Functional assays show no damaging effect or synonymous/intronic with no mRNA aberration." The evidence for this variant shows: functional studies demonstrate damaging LOF. 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 studies are available. 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 truncating. 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 condition." 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 indel in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "Computational evidence suggests no impact on gene or gene product." The evidence for this variant shows: predicted splice impact is minimal but variant is frameshift. Therefore, this criterion is not applied.
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 such information. 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." The evidence for this variant shows: not reported as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or intronic variant with no splice impact." The evidence for this variant shows: it is frameshift. Therefore, this criterion is not applied.