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"This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The MSH2 S743Ffs*7 variant is a truncating mutation in the MSH2 gene, a DNA mismatch repair protein. Functional evidence indicates that truncating mutations in MSH2 lead to the loss of normal mismatch repair function by disrupting the MutS domain, which is essential for the protein's activity. This disruption is likely to impair the protein's ability to bind mismatched nucleotides and dimerize, both of which are critical for its function. Therefore, the MSH2 S743Ffs*7 variant is functionally characterized as damaging.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.05 | -14 bp |
| Donor Loss (DL) | 0.01 | 57 bp |
| Acceptor Gain (AG) | 0.11 | 18 bp |
| Donor Gain (DG) | 0.0 | 223 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) ≤ codon 891 in MSH2." The evidence for this variant shows: the c.2227dup (S743Ffs*7) frameshift introduces a premature stop at codon 750, which is ≤891. Therefore, this criterion is applied at Very Strong strength because the variant is predicted to result in loss of function in a gene where LOF is a known disease mechanism.
PS1 (Not Applied)
According to VCEP 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 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 occurrence 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: in vitro and in vivo studies demonstrate loss of MSH2 mismatch repair activity due to truncation disrupting the MutS domain. Therefore, this criterion is applied at Moderate strength because a functional MMR defect is demonstrated.
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 prevalence 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 functional domain without benign variation." The evidence for this variant shows: no specific hot spot or critical domain annotation beyond LOF. 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 dataset." The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
According to VCEP guidelines, PM3 is for recessive disorders requiring trans observations. The evidence for this variant shows: Lynch syndrome is autosomal dominant, and no trans observations are applicable. 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 frameshift leading to truncation, which is covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change is established Pathogenic." The evidence for this variant shows: it is a frameshift, 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, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo or family data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP 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, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Predicted splice defect (delta score ≥0.2) or high prior probability for missense." The evidence for this variant shows: in silico scores are below thresholds and variant is frameshift. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Tumor MSI-H and loss of protein expression consistent with variant location." The evidence for this variant shows: no tumor data are available. 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 evidence is not available for independent evaluation." The evidence for this variant shows: ClinVar lists it as Pathogenic by one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable source reports pathogenicity.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "GnomAD v4 AF ≥0.001." The evidence for this variant shows: frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "GnomAD v4 AF ≥0.0001 and <0.001." The evidence for this variant shows: frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Co-occurrence in trans with a known pathogenic variant without CMMRD features." The evidence for this variant shows: no co-occurrence data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Calibrated functional assays showing benign effect." The evidence for this variant shows: no benign functional data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data 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 LOF causes disease." The evidence for this variant shows: it is LOF. 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 gene." 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 repetitive region." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "No predicted splice impact or low missense prior." The evidence for this variant shows: not applicable to frameshift. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Tumors with MSS and/or inconsistent protein loss." The evidence for this variant shows: no tumor phenotype 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." The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Silent or intronic variant with no splicing impact." The evidence for this variant shows: it is frameshift. Therefore, this criterion is not applied.