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
OpenThe p.I611T variant (also known as c.1832T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1832. The isoleucine at codon 611 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a cohort of patients with pancreatic ductal adenocarcinoma (PDAC) unselected for family history (Hu C et al. Cancer Epidemiol. Biomarkers Prev., 2016 Jan;25:207-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 611 of the MLH1 protein (p.Ile611Thr). This variant is present in population databases (rs141688321, gnomAD 0.007%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 26483394). ClinVar contains an entry for this variant (Variation ID: 820147). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
"This variant has been reported in ClinVar as Uncertain significance (2 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 | -97 bp |
| Donor Loss (DL) | 0.0 | 165 bp |
| Acceptor Gain (AG) | 0.01 | -60 bp |
| Donor Gain (DG) | 0.0 | 1 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) at or before codon 753 in MLH1...". The evidence for this variant shows: it is a missense change (I611T), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic...". The evidence for this variant shows: no known pathogenic MLH1 I611T with a different nucleotide. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong ≥4 de novo points; Strong 2–3 de novo points; Moderate 1 de novo point; Supporting 0.5 de novo points". The evidence for this variant shows: no de novo occurrence data. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong—Calibrated functional assays with functional odds for Pathogenicity >18.7; Moderate—Calibrated functional assays with odds >4.3; Supporting—odds >2.08". The evidence for this variant shows: no functional assay data available. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is 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 hotspot or domain information provided. 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: MAF = 0.000398% (3.98×10⁻⁶), which is below 1 in 50,000. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in population databases consistent with PM2.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Recessive disorder allele detection points...". The evidence for this variant shows: no evidence of trans with a pathogenic MLH1 variant. 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.". The evidence for this variant shows: it is a missense substitution with no length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change was classified as Pathogenic.". The evidence for this variant shows: no other missense at codon 611 characterized as pathogenic. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity.". The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in pedigrees meeting Bayes LR thresholds.". The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in gene with low rate of benign missense variation and for which missense is a common mechanism of disease.". The evidence for this variant shows: insufficient gene-specific missense tolerance data. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Missense variant with HCI prior >0.81 or predicted splice defect with SpliceAI >=0.2.". The evidence for this variant shows: no HCI prior provided and SpliceAI delta=0.01 (<0.2). Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Tumor MSI-H or loss of MMR protein expression in ≥1 appropriate tumors excluding MLH1 promoter methylation.". The evidence for this variant shows: no tumor or clinical phenotype 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 without evidence.". The evidence for this variant shows: ClinVar reports VUS only. 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 ≥0.001 (0.1%)'. The evidence for this variant shows: MAF 0.00000398, which is below 0.1%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001.' The evidence for this variant shows: MAF is below 0.0001. 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 without CMMRD features.". The evidence for this variant shows: no trans co-occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong—Calibrated functional assays with odds ≤0.05 or synonymous/intronic with no mRNA aberration.". The evidence for this variant shows: no functional assay or splicing data by assay. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation with disease in pedigrees (LR <0.05).". 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 are pathogenic.". The evidence for this variant shows: MLH1 has both truncating and some missense pathogenic variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with pathogenic variant for dominant disorder or in cis with pathogenic for recessive.". The evidence for this variant shows: no such 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 region without known function.". The evidence for this variant shows: it is a single amino acid substitution. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting Missense variant with HCI-prior <0.11 or intronic/synonymous with SpliceAI ≤0.1.". The evidence for this variant shows: HCI-prior not provided and variant is missense. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting—tumors inconsistent with pathogenic mechanism.". The evidence for this variant shows: no tumor or co-occurrence data. 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 without evidence.". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting—synonymous or intronic variant at or beyond −21/+7 with no splicing impact.". The evidence for this variant shows: it is missense. Therefore, this criterion is not applied.