MLH1 c.799_800del, p.Val267ArgfsTer39
NM_000249.4:c.799_800del
Pathogenic
The MLH1 c.799_800del (V267Rfs*39) variant is a truncating mutation resulting in loss of mismatch repair function, absent from population databases and supported by functional evidence. Application of PVS1_Very Strong, PS3_Moderate, and PM2_Supporting yields a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.799_800del
Protein Change
V267Rfs*39
Location
Exon 10
(Exon 10 of 19)
5'Exon Structure (19 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 267 in gene MLH1
Variant interpretation based on transcript NM_000249.4
Genome Browser
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HGVS InputNM_000249:c.799_800del
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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 267 in gene MLH1
Functional Summary
The MLH1 V267Rfs*39 variant is a truncating mutation that results in the loss of MLH1 expression, impairing its ability to bind PMS2. This disruption affects PMS2's DNA binding during damage repair, leading to impaired endonuclease function in DNA mismatch repair. Functional studies in MLH1-deficient mice show spontaneous development of gastrointestinal tumors and thymic lymphomas, with increased mutation burden indicative of mismatch repair inactivation. This evidence supports a damaging effect of the MLH1 V267Rfs*39 variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 Very Strong 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 frameshift (V267Rfs*39) resulting in a PTC well before codon 753 in MLH1, predicted to undergo NMD and causing loss of function. Therefore, this criterion is applied at Very Strong strength because the truncating variant is in a gene where LOF is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies when a different nucleotide change yields the same amino acid change previously established as pathogenic. The evidence for this variant shows: it is a novel frameshift, not a missense change at the same residue. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies to confirmed de novo occurrences. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, PS3 Moderate is: "MMR function defect following functional assay flowchart". The evidence for this variant shows: functional studies demonstrate loss of MLH1 expression, impaired PMS2 binding and DNA mismatch repair inactivation in cell and mouse models. Therefore, this criterion is applied at Moderate strength because well-established functional assays show a damaging effect on the gene product.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires statistically significant case-control enrichment. The evidence for this variant shows: no case-control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hot spots or critical domains. The evidence for this variant shows: no hotspot or critical domain annotation applies to this frameshift. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset". The evidence for this variant shows: it is not present in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. The evidence for this variant shows: MLH1‐associated Lynch syndrome is autosomal dominant and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to in-frame indels or stop loss that change protein length. The evidence for this variant shows: it is a frameshift leading to truncation, covered under PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues where a different pathogenic missense change is known. The evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo variants without confirmation. The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 applies to co-segregation with disease. 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, PP2 applies to missense variants in genes with low benign missense variation. The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 applies to multiple lines of computational evidence supporting a deleterious effect. The evidence for this variant shows: in silico predictions are inconclusive and the variant is a frameshift. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires tumor phenotype data. The evidence for this variant shows: no specific MSI or IHC tumor data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to variants reported as pathogenic by reputable sources without evidence. The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to high population frequency. The evidence for this variant shows: frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies to moderate population frequency. The evidence for this variant shows: frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to benign co-occurrence in trans for recessive disorders. The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 applies to well-established functional studies showing no damaging effect. The evidence for this variant shows: functional studies demonstrate damaging effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 applies to lack of segregation. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. The evidence for this variant shows: it is truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observed in cis or trans with pathogenic variant in a dominant disorder. The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP4 applies to multiple lines of computational evidence supporting a benign effect. The evidence for this variant shows: in silico evidence is inconclusive. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies to benign phenotype in tumors. The evidence for this variant shows: no conflicting tumor data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to low-quality pathogenic assertions. The evidence for this variant shows: no such assertions exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants with no impact. The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.