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 T441Yfs*2 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.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -41 bp |
| Donor Loss (DL) | 0.0 | 68 bp |
| Acceptor Gain (AG) | 0.0 | 30 bp |
| Donor Gain (DG) | 0.0 | -398 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 that c.1320dup (T441Yfs*2) creates a frameshift leading to a PTC well before codon 891. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP-defined loss-of-function mechanism threshold.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies to a missense change encoding the same amino acid as a different nucleotide change. This variant is a frameshift, not a missense substitution. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Very Strong Strength: ≥4 de novo points; Strong Strength: 2–3 de novo points; Moderate Strength: 1 de novo point; Supporting Strength: 0.5 de novo points.' There are no de novo data for this variant. Therefore, PS2 is not applied.
PS3 (Moderate)
According to VCEP guidelines, the rule for PS3 at Moderate strength is: 'Moderate Strength: Moderate calibrated functional assays with functional odds for pathogenicity >4.3 and ≤18.7 OR MMR function defect following functional assay flowchart.' The evidence for this variant shows well-established functional studies demonstrating loss of mismatch repair function due to disruption of the MutS domain. Therefore, PS3 is applied at Moderate strength because a mismatch repair defect has been demonstrated.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals compared to controls (case-control data). No case-control or prevalence data are available for this variant. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to missense variants at critical or well-established functional domains. This variant is a frameshift leading to truncation, not a missense change. Therefore, PM1 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 shows the variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength due to its absence in population databases.
PM3 (Not Applied)
According to VCEP guidelines, PM3 addresses recessive inheritance with trans observations. Lynch syndrome due to MSH2 is autosomal dominant and no trans evidence is relevant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to in-frame indels or protein length changes not predicted to cause loss of function. This variant is predicted to cause loss of function and is covered by PVS1. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 applies to novel missense changes at residues with other pathogenic missense variants. This variant is a frameshift. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines, PM6 addresses presumed de novo occurrences without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 applies to segregation data. No co-segregation data are provided. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to VCEP guidelines, PP2 applies to missense variants in genes with low benign missense variation. This is a frameshift variant. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, PP3 requires multiple in silico predictions of deleterious effect. SpliceAI predicts no splicing impact (delta score 0), and no pathogenic computational predictions are present. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies to tumor phenotype data (MSI-H or loss of MMR protein). No tumor phenotype data are available. Therefore, PP4 is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' ClinVar lists this variant as Pathogenic by one clinical laboratory. Therefore, PP5 is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies when allele frequency ≥0.001 in gnomAD v4. The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies when allele frequency ≥0.0001 and <0.001 in gnomAD v4. The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies to co-occurrence in trans with pathogenic variants in clinical contexts. No such data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 applies when functional assays show no damaging effect. The evidence shows a functional defect. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies to lack of segregation data. No segregation data are provided. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to VCEP guidelines, BP1 applies to missense variants in genes where only loss-of-function is known. This variant is frameshift. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies to observations in trans with a pathogenic variant in a recessive gene. Lynch syndrome is dominant. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is frameshift. Therefore, BP3 is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: 'Supporting when SpliceAI predicts no splicing impact (delta score ≤0.1).' SpliceAI delta score is 0, indicating no predicted splicing effect. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, BP5 applies to tumor data inconsistent with Lynch syndrome. No such data are available. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies when a reputable source reports a variant as benign without evidence. No such benign reports exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This variant is a frameshift. Therefore, BP7 is not applied.