MLH1 c.1190del, p.Leu397ArgfsTer4
NM_000249.4:c.1190del
Pathogenic
NM_000249.4:c.1190del (L397Rfs*4) in MLH1 is classified as Pathogenic based on a VCEP Very Strong PVS1 for truncating NMD-inducing variant, VCEP Moderate PS3 for confirmed MMR functional defect, VCEP Supporting PM2 for absence in controls, and Supporting PP5 for reputable pathogenic reports.
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
Loss-of-Function
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 DNA mismatch repair due to disrupted endonuclease function. Functional studies in mice deficient in MLH1 show spontaneous development of gastrointestinal tumors and thymic lymphomas, with increased mutation burden, indicating a loss-of-function effect. Therefore, the functional evidence supports 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, the rule for PVS1 is: “Very Strong Nonsense/frameshift variant introducing Premature Termination Codon at or before codon 753 in MLH1.” The evidence for this variant shows: NM_000249.4:c.1190del (L397Rfs*4) introduces a stop codon well before codon 753 and is predicted to undergo NMD. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP-defined threshold for a truncating variant leading to loss of function in MLH1.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: “Strong A predicted missense substitution encoding the same amino acid change with a different nucleotide change previously established as pathogenic.” The evidence for this variant shows: it is a frameshift variant, not a missense. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: “Very Strong/Strong/Moderate/Supporting De novo occurrence confirmed or assumed.” The evidence for this variant shows: no parental testing or de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 is: “Moderate MMR function defect following functional assay flowchart.” The evidence for this variant shows: functional studies demonstrate loss of MLH1 expression, failure to bind PMS2, and impaired mismatch repair in mouse models. Therefore, this criterion is applied at Moderate strength because the variant shows a confirmed MMR functional defect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: “Strong Prevalence in affected individuals statistically increased compared to controls.” The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: “Moderate Located in a mutational hot spot or critical functional domain without benign variation.” The evidence for this variant shows: it is a frameshift outside defined hotspots or domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
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: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because it is absent/rare in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: “Moderate/Strong/Very Strong Evidence for recessive disorders when variant detected in trans with a pathogenic variant.” The evidence for this variant shows: MLH1-related Lynch syndrome is autosomal dominant and no trans data are present. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: “Moderate Protein length changes due to in-frame indels or stop-loss variants.” The evidence for this variant shows: it is a frameshift causing a premature stop, covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: “Moderate Missense at same residue as a known pathogenic missense.” The evidence for this variant shows: it is not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: “Supporting Assumed de novo without confirmation of paternity and maternity.” The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: “Supporting/Moderate/Strong Co-segregation with disease in multiple affected family members.” The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: “Supporting Missense in gene with low rate of benign missense and pathogenicity defined by missense.” The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: “Supporting Multiple lines of computational evidence support a deleterious effect.” The evidence for this variant shows: in silico tools (CADD, SpliceAI) do not predict a deleterious effect beyond the frameshift. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: “Supporting/Moderate/Strong Tumor phenotype consistent with MLH1 variant with exclusion of MLH1 promoter methylation.” The evidence for this variant shows: no tumor or MSI data are available. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: “Supporting Reputable source recently reports variant as pathogenic but the evidence is not available for independent review.” The evidence for this variant shows: it is reported as Pathogenic by three clinical laboratories in ClinVar and by the InSiGHT expert panel. Therefore, this criterion is applied at Supporting strength because it is reported by reputable sources without available primary data.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: “Stand Alone Allele frequency ≥0.1% in gnomAD v4 excludes pathogenicity.” The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: “Strong Allele frequency 0.01–0.1% in gnomAD v4 excludes pathogenicity.” The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: “Strong Co-occurrence in trans with a pathogenic variant in same gene in a patient without CMMRD.” The evidence for this variant shows: no co-occurrence data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: “Strong/Supporting Well-established functional studies show no damaging effect.” The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: “Strong/Supporting Lack of co-segregation in multiple affected family members.” The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: “Supporting Missense variant in gene where only truncating variants cause disease.” The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: “Supporting Observed in trans with a pathogenic variant for a dominantly inherited disorder.” The evidence for this variant shows: no trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: “Supporting In-frame indel in repetitive region without known function.” The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: “Supporting Multiple lines of computational evidence support no impact.” The evidence for this variant shows: computational tools are irrelevant for a truncating variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: “Supporting Variant found in a case with an alternate molecular basis for disease.” The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: “Supporting Reputable source reports benign.” The evidence for this variant shows: reported as Pathogenic. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: “Supporting Synonymous or intronic variant with no splicing impact.” The evidence for this variant shows: it is neither synonymous nor intronic. Therefore, this criterion is not applied.