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
OpenThis sequence change affects an acceptor splice site in intron 13 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15309712, 31615790, 32587781). ClinVar contains an entry for this variant (Variation ID: 90930). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Likely pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.98 | 2 bp |
| Donor Loss (DL) | 0.18 | 249 bp |
| Acceptor Gain (AG) | 0.3 | 16 bp |
| Donor Gain (DG) | 0.0 | -336 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 Very Strong Strength is: "Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD." The evidence for this variant shows that NM_000251.3:c.2211-2A>T is at the −2 splice acceptor position in MSH2 and is predicted to abolish the canonical splice site leading to exon skipping and a frameshift subject to NMD. Therefore, PVS1 is applied at Very Strong strength because this is a canonical splice site variant predicted to result in loss of function in a gene where LOF is a known mechanism of disease.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 Strong Strength is: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect)." The evidence for this variant shows it is a splice site alteration, not a missense substitution encoding an amino acid change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 Strong Strength is: "2 or 3 de novo points." The evidence for this variant shows no documented de novo occurrence or parental testing. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 Strong Strength is: "Calibrated functional assays with functional odds for Pathogenicity > 18.7." The evidence for this variant shows no functional assay data characterizing its effect on MSH2 function. Therefore, PS3 is not applied.
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 comparing affected versus control frequencies. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 Moderate Strength 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 affects the splice acceptor site rather than a protein domain hot spot. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 Supporting Strength is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows it is absent from population databases including gnomAD. Therefore, PM2 is applied at Supporting strength because the variant is not observed in large control cohorts.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 Moderate Strength is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows no data regarding recessive trans occurrences, and Lynch syndrome is autosomal dominant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 Moderate Strength is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region." The evidence for this variant shows a splice site alteration rather than an in-frame protein length change. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 Moderate Strength is: "Missense change at an amino acid residue where a different missense change was classified as Pathogenic." The evidence for this variant shows a splice site alteration, not a missense change. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 Supporting Strength is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows no de novo data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 Supporting Strength is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows no segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 Supporting Strength is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism." The evidence for this variant shows a splice site alteration. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 Supporting Strength is: "Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥ 0.2." However, VCEP specifies that PP3 should not be combined with PVS1 for canonical splice site variants. The evidence for this variant shows a SpliceAI score of 0.98, but PVS1 has been applied. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 Supporting Strength is: "1 CRC/Endometrial MSI-H tumor with loss of MMR protein expression consistent with gene location." The evidence for this variant shows no tumor phenotype or MSI/MMR data. Therefore, PP4 is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 Supporting Strength is: "Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows ClinVar entries from multiple clinical laboratories and the InSiGHT expert panel classifying it as Likely Pathogenic or Pathogenic. Therefore, PP5 is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 Stand-Alone Strength is: "GnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%)." The evidence for this variant shows an allele frequency of 0% in controls, below the threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 Strong Strength is: "GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001." The evidence for this variant shows absence in gnomAD. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 Strong Strength is: "Co-occurrence in trans with a known pathogenic variant in the same gene in a patient meeting criteria." The evidence for this variant shows no reported in trans occurrences. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 Strong Strength is: "Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05 or synonymous/intronic with no mRNA aberration." The evidence for this variant shows no functional assay demonstrating lack of effect. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 Strong Strength is: "Lack of segregation in affected family members." The evidence for this variant shows no segregation data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 Supporting Strength is: "Missense variant in gene where only truncating variants cause disease." The evidence for this variant shows a splice defect, not a missense variant. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 Supporting Strength is: "Observed in trans with a pathogenic variant in a gene for a dominant disorder." The evidence for this variant shows no such co-occurrence. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 Supporting Strength is: "In-frame insertions/deletions in a repetitive region without a known function." The evidence for this variant shows a splice site alteration. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 Supporting Strength is: "SpliceAI predicts no splicing impact with delta score ≤ 0.1." The evidence for this variant shows a SpliceAI score of 0.98 indicating high impact. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 Supporting Strength is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows no alternate genetic explanation. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 Supporting Strength is: "Reputable source reports variant as benign, but evidence is not available." The evidence for this variant shows only pathogenic assertions. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 Supporting Strength is: "Synonymous or intronic variant at or beyond −21/+7 with no splicing impact." The evidence for this variant shows it is at −2 and disrupts splicing. Therefore, BP7 is not applied.