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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 13 bp |
| Donor Loss (DL) | 0.0 | 36 bp |
| Acceptor Gain (AG) | 0.71 | 0 bp |
| Donor Gain (DG) | 0.0 | -227 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Variants at IVS±1 or IVS±2…' The evidence for this variant shows it is a duplication spanning IVS–11 to exon boundary (non‐canonical splice site). Therefore, this criterion is not applied because the variant does not occur at the canonical +/–1 or +/–2 positions.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Variants affecting the same non‐canonical splice nucleotide as a confirmed pathogenic splice variant…' The evidence for this variant shows a unique intronic duplication not matching any known pathogenic splice variant. 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)…' The evidence for this variant shows no data on de novo occurrence or parental testing. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well‐established functional studies show a deleterious effect.' The evidence for this variant shows no functional assay data. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows no case‐control or case series data. 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 localization to a defined hotspot or domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.' The evidence for this variant shows MAF=0% (absent) in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant in a recessive disorder.' The evidence for this variant shows no trans observations and MSH2‐associated disease is autosomal dominant. 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.' The evidence for this variant shows an intronic duplication with unknown impact on coding sequence. 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 no amino acid 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.' The evidence for this variant shows no de novo or parental data. 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. 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 an intronic duplication, not a missense change. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Predicted splice defect for non‐canonical splicing nucleotides using SpliceAI with delta score ≥ 0.2.' The evidence for this variant shows SpliceAI acceptor gain score = 0.71. Therefore, this criterion is applied at Supporting strength because the variant is predicted to alter splicing.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: 'CRC/Endometrial MSI‐H tumors and/or loss of MMR protein expression consistent with variant.' The evidence for this variant shows no tumor MSI or IHC data. 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 no such reports. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'GnomAD v4 filtering allele frequency ≥ 0.001.' 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 filtering allele frequency ≥ 0.0001 and < 0.001.' 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 a known pathogenic variant in LS without CMMRD.' The evidence for this variant shows no co‐occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well‐established functional studies show no deleterious effect.' The evidence for this variant shows no functional assay data. 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 data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in gene where only truncating variants cause disease.' The evidence for this variant shows an intronic duplication, not a missense change. 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 disorder.' 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 deletions/insertions in repetitive regions without known function.' The evidence for this variant shows an intronic duplication of unknown repetitive context. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'SpliceAI predicts no splicing impact with delta score ≤ 0.1.' The evidence for this variant shows SpliceAI delta = 0.71. 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 alternate diagnosis. 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 such source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous or intronic variant at or beyond –21/ +7 with no splicing impact.' The evidence for this variant shows location at –11 and predicted splicing impact. Therefore, this criterion is not applied.