About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.688G>C, p.(Glu230Gln)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen MLH1 VCEP v2.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at very low frequency in gnomAD v4.1 at 2/1576948 alleles (AF 1.26827e-06), which is below the MLH1 PM2_Supporting threshold of 0.00002.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
For this MLH1 missense variant, the HCI prior probability is 0.0581, which is below the BP4 threshold of 0.11 and supports BP4_Supporting. REVEL is 0.627 and BayesDel is 0.158729, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.
Recorded classification: Not classified
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,576,948 alleles
gnomAD v4.1: 2 / 1,576,948 alleles. Recorded AF 1.26827e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1837e-05; MAF= 0.00318%, 1/31410 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4792e-05; MAF= 0.00648%, 1/15434 alleles, homozygotes = 0).
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
4 reported laboratory submissions
4 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MLH1 VCEP v2.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MLH1 NM_000249.4:c.688G>C (p.Glu230Gln; p.E230Q) variant has been reported in ClinVar as a variant of uncertain significance with four clinical laboratory submissions.
This variant is present at very low frequency in population databases, including gnomAD v4.1 at 2/1576948 alleles (AF 1.26827e-06; grpmax FAF 2.9e-07) and gnomAD v2.1 at 1/31410 alleles (AF 3.1837e-05), which is below the MLH1 PM2_Supporting threshold of 0.00002 in gnomAD v4.
No variant-specific calibrated functional assay result for p.Glu230Gln was identified in the reviewed mismatch repair functional assay references.
For this MLH1 missense variant, the HCI prior probability is 0.0581, below the BP4 threshold of 0.11; REVEL is 0.627, BayesDel is 0.158729, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at very low frequency in gnomAD v4.1 at 2/1576948 alleles (AF 1.26827e-06), which is below the MLH1 PM2_Supporting threshold of 0.00002. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 AF 1.26827e-06
- 2 of 1576948 alleles
- Threshold <0.00002
Sources
BP4 SupportingFor this MLH1 missense variant, the HCI prior probability is 0.0581, which is below the BP4 threshold of 0.11 and supports BP4_Supporting. REVEL is 0.627 and BayesDel is 0.158729, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. Details ▾Hide ▴
Rule
MLH1 missense BP4 requires HCI prior probability <0.11.
Evidence considered
- HCI prior 0.0581
- REVEL 0.627
- BayesDel 0.158729
- SpliceAI max delta 0.04
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This is a missense substitution, not a nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or proven splice-abrogating variant, so PVS1 is not met under the MLH1-specific rules. Details ▾Hide ▴
Rule
MLH1-specific PVS1 applies to qualifying loss-of-function or proven splice-abrogating variants, not to this missense substitution.
Evidence considered
- Missense change p.Glu230Gln
- Generic PVS1 scaffold did not place this variant in a null-variant bucket
Sources
PP3 For this MLH1 missense variant, the HCI prior probability is 0.0581, which is below the PP3 thresholds of >0.68 for Supporting and >0.81 for Moderate. REVEL is 0.627 and BayesDel is 0.158729, but the MLH1 VCEP prioritizes the HCI prior for missense PP3/BP4. SpliceAI also predicts no significant splice impact, with a maximum delta score of 0.04, which is below the non-canonical splice PP3 threshold of 0.2. Details ▾Hide ▴
Rule
MLH1 missense PP3 requires HCI prior >0.68 for Supporting or >0.81 for Moderate; non-canonical splice PP3 requires SpliceAI >=0.2.
Evidence considered
- HCI prior 0.0581
- REVEL 0.627
- BayesDel 0.158729
- SpliceAI max delta 0.04
Sources
BA1 The gnomAD v4.1 grpmax filtering allele frequency is 2.9e-07, which is below the BA1 threshold of 0.001, so BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires gnomAD v4 grpmax filtering allele frequency >=0.001 and exclusion as a founder pathogenic variant.
Evidence considered
- gnomAD v4.1 grpmax FAF 2.9e-07
- Threshold 0.001
Sources
BS1 The gnomAD v4.1 grpmax filtering allele frequency is 2.9e-07, which is below the BS1 range of 0.0001 to <0.001, so BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires gnomAD v4 grpmax filtering allele frequency >=0.0001 and <0.001 and exclusion as a founder pathogenic variant.
Evidence considered
- gnomAD v4.1 grpmax FAF 2.9e-07
- Threshold 0.0001 to <0.001
Sources
Not assessed · 11 · no assessment recorded
PS1 No previously established MLH1 pathogenic or likely pathogenic variant causing the same amino acid change with a different nucleotide change was identified in the available evidence, so PS1 was not applied. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic or likely pathogenic variant, subject to MLH1 VCEP rule details.
Evidence considered
- ClinVar record reviewed
- MLH1 VCEP PS1 rule reviewed
Still missing
- Direct review of any additional same-amino-acid alternate-nucleotide assertions would be needed before applying PS1.
Sources
PS2 No confirmed de novo occurrence data with the point-based evidence required by the MLH1 VCEP were identified, so PS2 was not assessed. Details ▾Hide ▴
Rule
Apply only when de novo points are supported by confirmed parentage and phenotype-specific evidence.
Evidence considered
- MLH1 VCEP PS2 point framework reviewed
Still missing
- Documented maternity and paternity with phenotype details would be needed to score de novo points.
Sources
PS3 No variant-specific calibrated functional assay result for p.Glu230Gln was identified in the reviewed mismatch repair functional assay references, so PS3 was not applied. Details ▾Hide ▴
Rule
Apply PS3 only for calibrated functional evidence meeting MLH1 VCEP thresholds.
Evidence considered
- No match for c.688G>C or p.Glu230Gln in local MMR functional assay spreadsheet
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- Direct review of any newly identified published functional assays would be needed to determine whether PS3 can be applied and at what strength.
Sources
PM3 No confirmed in trans observations with an established pathogenic MLH1 variant and no PM3 point-based evidence were identified, so PM3 was not assessed. Details ▾Hide ▴
Rule
Apply only when in trans observations support the MLH1 VCEP PM3 point system.
Evidence considered
- MLH1 VCEP PM3 point framework reviewed
Still missing
- Phase-confirmed biallelic observations with phenotype information would be needed to assign PM3 points.
Sources
PM5 No eligible same-residue pathogenic or likely pathogenic missense comparator at codon 230 was established from the available evidence, so PM5 was not applied. Details ▾Hide ▴
Rule
Classic same-residue PM5 requires an established pathogenic or likely pathogenic missense comparator and PP3 support under the MLH1 VCEP rules.
Evidence considered
- PM5 candidate artifact did not yield eligible comparators
- No match for c.688G>C or p.Glu230Gln in local VCEP pilot spreadsheet
Still missing
- Direct confirmation of any same-residue MLH1 expert-panel comparator variants would be needed before applying PM5.
Sources
PP1 No segregation data with a calculable Bayes likelihood ratio were identified, so PP1 was not assessed. Details ▾Hide ▴
Rule
Apply only when co-segregation data meet MLH1 VCEP Bayes likelihood-ratio thresholds.
Evidence considered
- MLH1 VCEP PP1 likelihood-ratio framework reviewed
Still missing
- Pedigree-based segregation data would be needed to score PP1 under the MLH1 VCEP framework.
Sources
PP4 No tumor MSI, mismatch repair immunohistochemistry, or MLH1 promoter methylation data were identified to support the MLH1-specific PP4 phenotype rule, so PP4 was not assessed. Details ▾Hide ▴
Rule
Apply only when the required tumor MSI and/or MMR protein expression evidence is available under the MLH1 VCEP thresholds.
Evidence considered
- MLH1 VCEP PP4 tumor-based framework reviewed
Still missing
- Tumor MSI and/or loss of protein expression data
- with MLH1 promoter methylation exclusion where relevant
- would be needed.
Sources
BS2 No confirmed in trans co-occurrence with a known pathogenic MLH1 variant in an individual meeting the MLH1 VCEP BS2 conditions was identified, so BS2 was not assessed. Details ▾Hide ▴
Rule
Apply only when the specified in trans co-occurrence and clinical conditions are met.
Evidence considered
- MLH1 VCEP BS2 rule reviewed
Still missing
- Phase-confirmed co-occurrence data with appropriate clinical context would be needed.
Sources
BS3 No variant-specific calibrated functional evidence showing retained mismatch repair function was identified in the reviewed functional assay references, so BS3 was not applied. Details ▾Hide ▴
Rule
Apply BS3 only for calibrated benign functional evidence or qualifying proficient function under the MLH1 VCEP framework.
Evidence considered
- No match for c.688G>C or p.Glu230Gln in local MMR functional assay spreadsheet
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- Direct review of any newly identified published functional assays would be needed to determine whether BS3 can be applied and at what strength.
Sources
BS4 No non-segregation data with a calculable Bayes likelihood ratio were identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
Apply only when lack of segregation meets MLH1 VCEP Bayes likelihood-ratio thresholds.
Evidence considered
- MLH1 VCEP BS4 likelihood-ratio framework reviewed
Still missing
- Pedigree-based non-segregation data would be needed to score BS4 under the MLH1 VCEP framework.
Sources
BP5 No tumor findings meeting the MLH1-specific BP5 conditions, such as multiple MSS or inconsistent mismatch repair protein results or qualifying MLH1 methylation/BRAF evidence, were identified, so BP5 was not assessed. Details ▾Hide ▴
Rule
Apply only when the required benign tumor evidence is available under the MLH1 VCEP thresholds.
Evidence considered
- MLH1 VCEP BP5 tumor-based framework reviewed
Still missing
- Tumor molecular data would be needed to determine whether BP5 applies.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPPS4 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks PS4 as not applicable
Sources
PM1 VCEPPM1 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks PM1 as not applicable
Sources
PM4 VCEPPM4 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks PM4 as not applicable
Sources
PM6 VCEPPM6 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks PM6 as not applicable
Sources
PP2 VCEPPP2 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks PP2 as not applicable
Sources
PP5 VCEPPP5 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks PP5 as not applicable
Sources
BP1 VCEPBP1 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks BP1 as not applicable
Sources
BP2 VCEPBP2 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks BP2 as not applicable
Sources
BP3 VCEPBP3 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks BP3 as not applicable
Sources
BP6 VCEPBP6 is not used in the MLH1 VCEP specification for this gene framework. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- MLH1 VCEP marks BP6 as not applicable
Sources
BP7 N/ABP7 is restricted to synonymous or qualifying intronic variants, and this variant is a missense substitution. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying intronic variants, not to missense substitutions.
Evidence considered
- Missense change p.Glu230Gln
Sources
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.4
- Coding (HGVS c.)
- NM_000249.4:c.688G>C
- Protein (HGVS p.)
- NP_000240.1:p.(Glu230Gln)
- GRCh38
- chr3:37014442 G>C
- GRCh37
- chr3:37055933 G>C
- ClinVar
- 483554
Gene diagram
Every interpreted variant in MLH1, mapped onto the exon structure of NM_000249.4. Select a row to find it on the plot.
MLH1NM_000249.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MLH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2 / 1,576,948 alleles
AF 1.27e-06 · 0 homozygotes · FAF 2.9e-07
gnomAD v2.1
1 / 31,410 alleles
AF 3.18e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.3e-06 · 2 / 1,576,948 alleles · 0 hom · FAF 2.9e-07
| European (non-Finnish)2 / 1,146,320 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,410 alleles · 0 hom
| European (non-Finnish)1 / 15,434 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.26827e-06; MAF= 0.00013%, 2/1576948 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74471e-06; MAF= 0.00017%, 2/1146320 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1837e-05; MAF= 0.00318%, 1/31410 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4792e-05; MAF= 0.00648%, 1/15434 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.627
- BayesDel
- 0.159
How the predictions were used
BP4 SupportingFor this MLH1 missense variant, the HCI prior probability is 0.0581, which is below the BP4 threshold of 0.11 and supports BP4_Supporting. REVEL is 0.627 and BayesDel is 0.158729, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04. Details ▾Hide ▴
Rule
MLH1 missense BP4 requires HCI prior probability <0.11.
Evidence considered
- HCI prior 0.0581
- REVEL 0.627
- BayesDel 0.158729
- SpliceAI max delta 0.04
Sources
PP3 For this MLH1 missense variant, the HCI prior probability is 0.0581, which is below the PP3 thresholds of >0.68 for Supporting and >0.81 for Moderate. REVEL is 0.627 and BayesDel is 0.158729, but the MLH1 VCEP prioritizes the HCI prior for missense PP3/BP4. SpliceAI also predicts no significant splice impact, with a maximum delta score of 0.04, which is below the non-canonical splice PP3 threshold of 0.2. Details ▾Hide ▴
Rule
MLH1 missense PP3 requires HCI prior >0.68 for Supporting or >0.81 for Moderate; non-canonical splice PP3 requires SpliceAI >=0.2.
Evidence considered
- HCI prior 0.0581
- REVEL 0.627
- BayesDel 0.158729
- SpliceAI max delta 0.04
Sources
BP7 N/ABP7 is restricted to synonymous or qualifying intronic variants, and this variant is a missense substitution. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying intronic variants, not to missense substitutions.
Evidence considered
- Missense change p.Glu230Gln
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.627. BayesDel score = 0.158729. HCI prior probability for pathogenicity = 0.0581. MAPP score = 4.41. Custom PP2 score = 0.715.
3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,576,948 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
4 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1564688410
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/483554/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37055933-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37014442-G-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.4%3Ac.688G…
- OncoKB ↗www.oncokb.org/gene/MLH1/E230Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH1+c.688G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.26827e-06; MAF= 0.00013%, 2/1576948 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74471e-06; MAF= 0.00017%, 2/1146320 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1837e-05; MAF= 0.00318%, 1/31410 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4792e-05; MAF= 0.00648%, 1/15434 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 483554)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.627. BayesDel score = 0.158729. HCI prior probability for pathogenicity = 0.0581. MAPP score = 4.41. Custom PP2 score = 0.715.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.