Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000179.2 | RefSeq Select | 4435 nt | 153–4235 |
| NM_000179.1 | Alternative | 4264 nt | 88–4170 |
| NM_000179.3 | MANE Select | 4265 nt | 90–4172 |
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) | 1.0 | 13 bp |
| Donor Loss (DL) | 0.05 | 102 bp |
| Acceptor Gain (AG) | 0.96 | 41 bp |
| Donor Gain (DG) | 0.01 | 262 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule/finding for PVS1 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 a deletion from c.3557-6 into the exon, outside the canonical ±1/2 splice sites. Therefore, this criterion is not applied because the variant does not affect the canonical splice dinucleotides covered by PVS1.
PS1 (Not Applied)
According to VCEP guidelines, the rule/finding for PS1 is: "Strong: A predicted missense substitution that encodes the same amino acid change as a previously established pathogenic variant (not a splice defect)." The evidence for this variant shows an intronic/exonic deletion predicted to affect splicing, not a missense change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There are no data on de novo status for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule/finding for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity > 18.7." No functional assay data are available for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls." No case-control or segregation data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." This variant is an intronic/exonic deletion outside known functional motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule/finding for PM2 is: "Supporting: 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.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." MSH6-associated Lynch syndrome is autosomal dominant, and no trans data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat regions." This variant affects splicing and its impact on protein length is not established. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule/finding for PM5 is: "Moderate: Missense change at an amino acid residue where a different missense change was classified as Pathogenic." This variant is not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." There are no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule/finding for PP1 is: "Co-segregation with disease in pedigree(s) with a combined likelihood ratio >2.08 (Supporting)." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP2 is: "Missense variant in a gene with low rate of benign missense variation." This variant is predicted to affect splicing, not a missense change. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting: Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥0.2." The evidence for this variant shows a SpliceAI delta score of 1.0 for acceptor loss. Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to VCEP guidelines, the rule/finding for PP4 is: "Supporting: 1 CRC/Endometrial MSI-H tumor with loss of MMR protein expression consistent with variant location." No tumor phenotype data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source reports variant as pathogenic without available evidence." This variant is not reported in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone: GnomAD v4 allele frequency ≥0.22%." The variant is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule/finding for BS1 is: "Strong: GnomAD v4 allele frequency ≥0.022% and <0.22%." The variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule/finding for BS2 is: "Strong: Co-occurrence in trans with a known pathogenic variant in LS gene in a patient without CMMRD." No co-occurrence data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule/finding for BS3 is: "Strong: Calibrated functional assays show no functional impact." No functional assay data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BS4 is: "Lack of co-segregation with disease in pedigree(s) with combined likelihood ratio <0.05." No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP1 is: "Missense variant in gene where only truncating variants cause disease." This variant affects splicing. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." No phasing or cis/trans data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP3 is: "In-frame deletion in a repetitive region without known function." This variant affects splicing and is not an in-frame deletion in a repeat. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP4 is: "Computational evidence suggests no impact (SpliceAI delta ≤0.1)." SpliceAI delta is 1.0, indicating impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP5 is: "Variant found in a case with an alternate molecular basis for disease." No such data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign without evidence." The variant is not reported as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP7 is: "Synonymous or intronic variant at or beyond –21/+7 with no splicing impact." This deletion overlaps –6/+? positions and is predicted to impact splicing. Therefore, this criterion is not applied.