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
OpenThis variant has been observed in an individual affected with Lynch syndrome (PMID: 20877318). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr678*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
"This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The MSH2 Y678* variant is a truncating mutation that results in the loss of normal mismatch repair function. This mutation disrupts the mismatch repair pathway by causing partial or complete loss of the MutS domain, which is essential for the protein's function. Consequently, this variant is functionally characterized as damaging, likely contributing to oncogenesis.
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) | 0.0 | -28 bp |
| Donor Loss (DL) | 0.01 | 176 bp |
| Acceptor Gain (AG) | 0.0 | 68 bp |
| Donor Gain (DG) | 0.0 | -14 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: it is a nonsense variant at codon 678 (Y678*), which is ≤ codon 891 and predicted to undergo nonsense-mediated decay in a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the truncation clearly disrupts MSH2 function via LOF.
PS1 (Not Applied)
According to standard ACMG, the rule for PS1 is: "Same amino acid change with different underlying nucleotide change previously established as Pathogenic." The evidence for this variant shows: Y678* is a novel nucleotide change introducing a stop codon, not a recurrent missense substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG, 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 (Strong)
According to VCEP guidelines, the rule for PS3 Strong is: "Calibrated functional assays with functional odds for Pathogenicity >18.7." The evidence for this variant shows: in vitro and in vivo assays demonstrate complete loss of MMR function and disruption of the MutS domain. Therefore, this criterion is applied at Strong strength because validated functional studies establish a damaging effect.
PS4 (Not Applied)
According to standard ACMG, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared to controls (case-control data)." 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, 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: although it truncates MSH2, there is no specific hot-spot annotation beyond general 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 not present in gnomAD. Therefore, this criterion is applied at Supporting strength because of absence from population controls.
PM3 (Not Applied)
According to standard ACMG, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: no trans observations reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG, 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/truncating variant covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG, the rule for PM5 is: "Missense change at an amino acid residue where a different pathogenic missense change has been observed." The evidence for this variant shows: it is a nonsense change, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG, the rule for PM6 is: "Assumed de novo 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, 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, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common disease mechanism." The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, computational evidence (BP4/PP3) is not combined with PVS1 for canonical LOF variants. The evidence for this variant shows: mixed in silico predictions but PVS1 overrides. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 requires tumor MSI-H or loss of MMR protein consistent with gene. The evidence for this variant shows: no tumor phenotype or IHC/MSI data. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG, 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 two clinical laboratories. Therefore, this criterion is applied at Supporting strength because of multiple reputable submissions.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Allele frequency ≥0.1% in gnomAD v4 excludes pathogenicity." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Allele frequency between 0.01% and <0.1% in gnomAD v4." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in trans with a known pathogenic variant in a patient with CRC after age 45 without CMMRD features." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG, BS3 is: "Well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG, 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, 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, BP2 is: "Observed in cis with a pathogenic variant." The evidence for this variant shows: no cis observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG, BP3 is: "In-frame indels in repetitive regions without functional impact." The evidence for this variant shows: it is not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 is: "SpliceAI predicts no splicing impact (Δ score ≤0.1) for intronic/synonymous variants or HCI-prior <0.11 for missense." The evidence for this variant shows: it is a nonsense variant and BP4 is not applied with PVS1. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG, BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG, BP6 is: "Reputable source reports variant as benign with unavailable evidence." The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG, BP7 is: "Synonymous or intronic variant with no splicing impact." The evidence for this variant shows: it is a nonsense variant, not synonymous/intronic. Therefore, this criterion is not applied.