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"This variant has been reported in ClinVar as Uncertain significance (4 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) | 0.01 | 1 bp |
| Donor Loss (DL) | 0.0 | 106 bp |
| Acceptor Gain (AG) | 0.02 | -8 bp |
| Donor Gain (DG) | 0.04 | 102 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical ±1/2 splice) in MLH1. The evidence for this variant shows it is a missense change (E230Q). Therefore, this criterion is not applied because the variant does not introduce a premature stop or affect canonical splice sites.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 requires the same amino acid change as a known pathogenic variant. There is no report of a different nucleotide change encoding E230Q as pathogenic in MLH1. Therefore, PS1 is not applied due to lack of an established pathogenic variant with the same amino acid change.
PS2 (Not Applied)
According to VCEP disease-specific de novo guidelines, PS2 requires confirmed de novo occurrence. The evidence for this variant shows no de novo data. Therefore, PS2 is not applied because parental testing for de novo status is unavailable.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 requires well-validated functional studies showing a deleterious effect. The evidence for this variant shows no functional assay data. Therefore, PS3 is not applied due to absence of functional characterization.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 requires statistical case-control or phenotype prevalence data. The evidence for this variant shows no case-control or cohort data. Therefore, PS4 is not applied because statistical association data are missing.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 applies to variants in mutational hotspots or critical functional domains. The evidence for this variant shows E230 is not located in a known hotspot or annotated functional domain of MLH1. Therefore, PM1 is not applied.
PM2 (Not Applied)
According to VCEP guidelines, PM2_Supporting requires absence or extremely rare frequency (<1/50,000 alleles) in gnomAD. The evidence for this variant shows MAF ≈0.0000318 (1/31,410), which is above the 1/50,000 (0.00002) threshold. Therefore, PM2 is not applied because the allele frequency does not meet the VCEP rarity criterion.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies to recessive disorders with confirmed trans observations. The evidence for this variant shows no data on phase or compound heterozygosity. Therefore, PM3 is not applied due to absence of allelic configuration data.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to in-frame indels or stop-loss variants altering protein length. The evidence for this variant shows a single amino acid substitution without length change. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies when a different missense change at the same residue is pathogenic. The evidence for this variant shows no other pathogenic missense at E230 in MLH1. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines, PM6 covers unconfirmed de novo occurrences. The evidence for this variant shows no de novo data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 requires co-segregation in families. The evidence for this variant shows no family segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies in genes where missense variants are a common mechanism and benign variation is low. MLH1 has pathogenic and benign missense variants, but no specific VCEP rule applies. The evidence for this variant does not support gene-specific criteria. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 requires HCI prior >0.68 or SpliceAI ≥0.2. The evidence for this variant shows mixed in silico results and SpliceAI 0.04 (<0.2). Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 requires tumor MSI-high or loss of MMR expression consistent with MLH1. The evidence for this variant shows no tumor phenotype data. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 requires reputable source classification as pathogenic. The evidence for this variant shows ClinVar entries as VUS. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 requires allele frequency ≥0.1% in gnomAD. The evidence for this variant shows MAF 0.00318%, which is below 0.1%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies for allele frequency ≥0.01% and <0.1%. The evidence for this variant shows MAF 0.00318%, which is below 0.01%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 requires observation in healthy adults with no LS phenotype in trans with a pathogenic variant. The evidence for this variant shows no such data. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, BS3 requires functional studies showing no impact or calibrated odds ≤0.05. The evidence for this variant shows no functional assays. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 requires lack of segregation. The evidence for this variant shows no family data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense in genes where only truncating variants cause disease. MLH1 pathogenicity includes missense. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant for a dominant disorder. The evidence for this variant shows no such observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is a missense SNV. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, BP4 supports no impact when SpliceAI ≤0.1 and HCI prior <0.11. The evidence for this variant shows SpliceAI 0.04 and mixed in silico predicting overall benign impact. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, BP5 requires observation in tumors inconsistent with LS. The evidence for this variant shows no tumor data. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 requires reputable source classification as benign. The evidence for this variant shows ClinVar entries as VUS. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to synonymous/intronic variants at non-canonical positions. This variant is missense. Therefore, BP7 is not applied.