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"This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 247 bp |
| Donor Loss (DL) | 0.0 | 459 bp |
| Acceptor Gain (AG) | 0.0 | -76 bp |
| Donor Gain (DG) | 0.0 | 68 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 1341 in MSH6 ...". The evidence for this variant shows it is a synonymous (silent) change (P1161=) and does not introduce a PTC or alter splicing. Therefore, this criterion is not applied because the variant type does not meet the rule.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established Pathogenic variant but by a different nucleotide change." The evidence for this variant shows it is synonymous and does not change the amino acid. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is based on de novo occurrences. No de novo data are available for this variant. 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 on the gene or gene product." No functional studies have been performed on this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Increased prevalence in affected individuals compared to controls." No case-control or prevalence data are available. 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 or well‐studied functional domain without benign variation." This variant is synonymous and not in a defined functional domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting – Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows a MAF of 0.000796% (2/251,398 alleles), which is <1/50,000. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in 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." This gene/variant is associated with a dominantly inherited syndrome and no trans observations are reported. 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 or stop‐loss." This is a synonymous variant that does not alter protein length. 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 missense change is pathogenic." This variant is synonymous. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." No de novo evidence is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members." No segregation data are available. 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 and where missense is a common mechanism." This variant is synonymous. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, computational evidence for synonymous variants is captured under BP4, not PP3. SpliceAI predicts no impact, but no supporting evidence for pathogenicity. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is based on specific tumor phenotype data. No tumor phenotype or MSI/IHC data are provided. 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, but evidence is not available." No such reports exist. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone – gnomAD v4 Grpmax filtering allele frequency ≥0.0022 (0.22%)." The variant MAF is 0.000796%, below the threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong – gnomAD v4 Grpmax filtering allele frequency ≥0.00022 and <0.0022." The MAF of 0.00000796 (0.000796%) is below 0.00022. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Co‐occurrence in trans with a pathogenic variant in LS cancer without CMMRD features." No such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong – Synonymous substitutions and intronic variants with no associated mRNA aberration as determined by assays." No mRNA assay data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members." No segregation studies are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where truncating variants cause disease." This variant is synonymous. 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 for a dominant disorder." Not applicable. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in repetitive regions." Not applicable for a synonymous change. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting – For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤0.1." SpliceAI gives a delta score of 0 for this variant. Therefore, this criterion is applied at Supporting strength because computational evidence indicates no effect on splicing.
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." No such conflicting case evidence is available. Therefore, BP5 is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting – Reputable source reports variant as benign, but evidence is not available to the laboratory." ClinVar reports this variant as Likely benign (4 labs) and Benign (1 lab). Therefore, this criterion is applied at Supporting strength.
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: "Supporting – A synonymous (silent) or intronic variant at or beyond –21/+7 (5′/3′ exonic)." This variant is synonymous and presumed distant from splice junctions. Therefore, this criterion is applied at Supporting strength.