MLH1 c.1190del, p.Leu397ArgfsTer4
NM_000249.4:c.1190del
Pathogenic
This frameshift variant causes premature truncation of MLH1 (PVS1_VeryStrong), is absent from controls (PM2_Supporting), shows functional evidence of MMR defect (PS3_Moderate), and is reported as pathogenic by reputable sources (PP5_Supporting), consistent with a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
Genetic Information
Gene & Transcript Details
Gene
MLH1
Transcript
NM_000249.4
MANE Select
Total Exons
19
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000249.3 | RefSeq Select | 19 exons | Forward |
| NM_000249.2 | Alternative | 19 exons | Forward |
Variant Details
HGVS Notation
NM_000249.4:c.1190del
Protein Change
L397Rfs*4
Location
Exon 12
(Exon 12 of 19)
5'Exon Structure (19 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 397 in gene MLH1
Variant interpretation based on transcript NM_000249.4
Genome Browser
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HGVS InputNM_000249:c.1190del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Pathogenic
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
3 Path
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change creates a premature translational stop signal (p.Leu397Argfs*4) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 10196371, 25559809). ClinVar contains an entry for this variant (Variation ID: 89673). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratories) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel.
Expert Panel Reviews
Pathogenic
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 397 in gene MLH1
Functional Summary
The MLH1 L397Rfs*4 variant is a truncating mutation that results in a premature stop codon, leading to loss of MLH1 expression. This loss prevents MLH1 from binding to PMS2, impairing the DNA mismatch repair process. Functional studies indicate that MLH1 deficiency is associated with increased mutation burden and spontaneous tumor development in mice, supporting a damaging effect of this variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 6.48
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines for MLH1, the rule for PVS1 is: "Very Strong: Nonsense/frameshift variant introducing Premature Termination Codon (PTC) at or before codon 753 in MLH1." The evidence shows NM_000249.4:c.1190delT (L397Rfs*4) introduces a PTC at codon 400, well before codon 753. Therefore, this criterion is applied at Very Strong strength because the frameshift results in a truncating LOF variant meeting VCEP PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: A predicted missense substitution that encodes the same amino acid change with a different nucleotide change previously established as Pathogenic." The evidence shows the variant is a frameshift resulting in a premature stop codon, not a missense substitution. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong: ≥4 de novo points." There are no de novo data available for this variant. Therefore, PS2 is not applied due to missing de novo information.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 (Moderate) is: "Moderate: MMR function defect following functional assay flowchart." The evidence shows loss of MLH1 expression, failure to bind PMS2, and increased mutation burden in functional studies, consistent with MMR defect. Therefore, PS3 is applied at Moderate strength because the variant demonstrably impairs MMR function.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence of variant in affected individuals is increased compared to controls." No case-control or prevalence data are available. Therefore, PS4 is not applied due to lack of case-control data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in mutational hot spot and/or critical functional domain without benign variation." There is no evidence that c.1190delT occurs in a mutational hotspot or critical domain beyond LOF. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for MLH1, the rule for PM2 is: "Supporting: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence shows the variant is not present in gnomAD. Therefore, PM2 is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Points for detection in trans with pathogenic variant in recessive disease." MLH1-related Lynch syndrome is autosomal dominant and no trans observations are relevant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss." This variant is a frameshift leading to premature truncation, not an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change is pathogenic." The variant is a frameshift, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Supporting: Unconfirmed de novo occurrence." There are no de novo data available. Therefore, PM6 is not applied due to missing de novo information.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, PP1 is not applied due to missing familial segregation information.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation." The variant is truncating, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Missense variant with in silico predictive evidence." The variant is truncating and canonical; no in silico splice or missense prediction applies. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for MLH1, the rule for PP4 (Strong) is: "Tumor MSI-H or IHC loss consistent with variant location in ≥3 tumors." No tumor phenotype or MSI/IHC data are available. Therefore, PP4 is not applied due to missing tumor phenotype data.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic but evidence is not available." ClinVar entries and the InSiGHT expert panel report this variant as Pathogenic. Therefore, PP5 is applied at Supporting strength because multiple reputable sources classify it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to gene-specific ACMG guidelines, the rule for BA1 is: "Stand Alone: allele frequency ≥0.1% in gnomAD." The variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to gene-specific ACMG guidelines, the rule for BS1 is: "Strong: allele frequency between 0.01% and 0.1% in gnomAD." The variant is absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Co-occurrence in trans with a pathogenic variant in a recessive CMMRD context." MLH1 Lynch syndrome is dominant; no such observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: calibrated functional assays show no damaging effect." Functional studies show damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation with disease in families." No segregation data are available. Therefore, BS4 is not applied due to missing segregation information.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in gene where only truncating variants cause disease." The variant is truncating; BP1 is for missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with pathogenic variant in dominant disorder." No such data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in repetitive region without functional impact." The variant is a frameshift. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Predicted no impact for intronic/synonymous variants." The variant is truncating; in silico benign predictions for missense/splicing are not relevant. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Alternate genetic cause for phenotype present." No such evidence is available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." ClinVar and InSiGHT do not report this variant as benign. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or intronic variant with no splice impact." The variant is a frameshift. Therefore, BP7 is not applied.