Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000249.4 | MANE Select | 2494 nt | 31–2301 |
| NM_000249.3 | RefSeq Select | 2662 nt | 199–2469 |
| NM_000249.2 | Alternative | 2524 nt | 61–2331 |
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) | 0.15 | 1 bp |
| Donor Loss (DL) | 0.0 | -241 bp |
| Acceptor Gain (AG) | 0.01 | 23 bp |
| Donor Gain (DG) | 0.0 | -82 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the PVS1 rule applies to canonical ±1/2 splice site variants or null variants in MLH1. The rule states: "Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame...". This variant is located at –23, outside the ±1/2 positions. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 applies when the variant causes the same amino acid change as a known pathogenic variant. This variant is intronic and does not alter an amino acid. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 applies for confirmed de novo occurrences. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 requires well‐established functional studies showing damaging effect. No functional assay data exist for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 applies when variant prevalence is significantly increased in affected individuals versus controls. No case-control or patient frequency data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 applies to variants in mutational hot spots or critical functional domains. This intronic variant does not lie in a known hotspot or domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 supporting applies when a variant is absent or extremely rare (<1 in 50,000 alleles) in gnomAD v4. The rule states: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The variant is observed at 1/250,612 alleles (MAF≈0.00000399), below the threshold. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies for variants observed in trans with a known pathogenic variant in recessive disorders. MLH1-related Lynch syndrome is dominant and no trans data exist. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop-loss. This variant is intronic with no coding effect. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues where other missense changes are pathogenic. This variant is intronic and not missense. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation. No de novo assumption data exist. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 applies to co-segregation with disease in families. No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rate of benign missense. This variant is intronic. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 supporting applies when SpliceAI predicts a delta score ≥0.2 for non-canonical splice variants. The rule states: "Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥ 0.2." The variant has a maximum SpliceAI delta of 0.15, below threshold. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies to tumor and expression data (MSI-H, loss of MMR protein). No tumor phenotype or IHC data are available. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies when reputable sources classify a variant as pathogenic. The variant is not reported in ClinVar or other databases. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 stand‐alone applies for gnomAD v4 filtering allele frequency ≥0.001. The variant’s highest frequency (0.000164) is below this. Therefore, BA1 is not applied.
BS1 (Strong)
According to VCEP guidelines, BS1 strong applies for gnomAD v4 filtering allele frequency ≥0.0001 and <0.001. The rule states: "GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001." The variant’s highest frequency is 0.000164, within this range. Therefore, BS1 is applied at Strong strength.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies for co-occurrence in trans with a known pathogenic MLH1 variant in a patient without CMMRD. No co-occurrence data exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, BS3 applies to well‐established functional studies showing no damaging effect. No such assays exist for this variant. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 applies to lack of segregation with disease. No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only loss-of-function is disease mechanism. This variant is intronic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when variant is observed in cis with a pathogenic variant. No cis data exist. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a single-nucleotide intronic substitution. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 supporting applies when SpliceAI predicts no splicing impact with delta ≤0.1. The rule states: "SpliceAI predicts no splicing impact with delta score ≤ 0.1." The variant’s maximum delta is 0.15, above threshold. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines, BP5 applies to tumor data inconsistent with MLH1 pathogenicity. No tumor or methylation data are available. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies when reputable sources classify a variant as benign. No such classifications exist. Therefore, BP6 is not applied.
BP7 (Supporting)
According to VCEP guidelines, BP7 supporting applies to intronic variants at or beyond –21 from the exon. The rule states: "A synonymous (silent) or intronic variant at or beyond -21/+7." This variant is at –23. Therefore, BP7 is applied at Supporting strength.