About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.1177C>A, p.(Leu393Ile)
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. 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
NM_000249.3:c.1177C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the InSiGHT VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
HCI prior probability for pathogenicity is 0.0225, meeting the InSiGHT VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors also suggest a benign or indeterminate effect: SpliceAI max delta 0.02 (no splicing impact), REVEL 0.415 (indeterminate), BayesDel -0.07 (indeterminate).
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 v2.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting benign; 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 13 not met · 0 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
NM_000249.3:c.1177C>A (p.Leu393Ile) in MLH1 is a missense substitution absent from gnomAD population databases (PM2_Supporting met) but with a low HCI prior probability of pathogenicity of 0.0225 (BP4_Supporting met).
The variant is absent from ClinVar and has not been observed in any publication. No variant-specific functional data, tumor phenotype data, segregation data, or de novo observations are available.
Multiple in silico predictors are indeterminate or benign: SpliceAI max delta 0.02 (no splicing impact), REVEL 0.415, BayesDel -0.07.
Under the InSiGHT MLH1 VCEP v2.0 framework, the evidence profile (PM2_Supporting + BP4_Supporting) is insufficient to reach a Likely Pathogenic or Likely Benign classification. The variant remains a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingNM_000249.3:c.1177C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the InSiGHT VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles).
- Absent from gnomAD v4.1 (0 alleles).
- Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
BP4 SupportingHCI prior probability for pathogenicity is 0.0225, meeting the InSiGHT VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors also suggest a benign or indeterminate effect: SpliceAI max delta 0.02 (no splicing impact), REVEL 0.415 (indeterminate), BayesDel -0.07 (indeterminate). Details ▾Hide ▴
Evidence considered
- HCI prior probability 0.0225 (<0.11 threshold for BP4_Supporting).
- SpliceAI max delta 0.02 (no predicted splice impact).
- REVEL 0.415
- BayesDel -0.07 (both indeterminate).
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No different nucleotide change encoding the same amino acid substitution (p.Leu393Ile) has been established as pathogenic by this VCEP. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no alternate nucleotide change at this codon classified as pathogenic by InSiGHT VCEP.
Sources
clinvar ↗vcep_vcep_pilot_variants_mmr
PS2 No de novo observations have been reported for NM_000249.3:c.1177C>A in the available literature or databases. Details ▾Hide ▴
Evidence considered
- No de novo data identified in literature or databases.
Still missing
- No case-level or family-level data available
- de novo status cannot be evaluated without clinical reports.
PS3 No variant-specific functional data are available for c.1177C>A (p.Leu393Ile). The variant is not listed in the InSiGHT VCEP pilot variants spreadsheet, and no calibrated functional assay results (CIMRA, CRISPR hESC, or other MMR functional assays) were identified for this substitution. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- Variant not included in VCEP pilot variant assessment
- no calibrated functional assay data identified
- OncoKB reports Unknown Oncogenic Effect.
Still missing
- Functional assay data (CIMRA or Rath 2022 CRISPR hESC) not available for this specific variant.
Sources
PM5 No missense change at amino acid residue 393 has been classified as pathogenic or likely pathogenic by this VCEP. The PM5 candidate search yielded zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- Zero same-residue (Leu393) comparator variants identified
- no VCEP-classified pathogenic missense at this position.
Sources
pm5_candidatesvcep_vcep_pilot_variants_mmr
PP1 No co-segregation data are available for this variant in any pedigree. Details ▾Hide ▴
Evidence considered
- No family or pedigree data available.
Still missing
- Co-segregation analysis requires pedigree data which were not available for this assessment.
PP3 HCI prior probability for pathogenicity is 0.0225, well below the InSiGHT VCEP PP3 thresholds (>0.81 for moderate, >0.68 for supporting). SpliceAI predicts no splicing impact (max delta score 0.02, below the 0.2 threshold). REVEL score is 0.415 (indeterminate). Details ▾Hide ▴
Evidence considered
- HCI prior probability 0.0225 (below PP3 thresholds of >0.68/0.81).
- SpliceAI max delta 0.02 (no predicted splice impact).
- REVEL score 0.415 (indeterminate).
- BayesDel score -0.07 (indeterminate).
Sources
PP4 No tumor data (MSI-H status, MMR protein expression, or MLH1 promoter methylation) are available for carriers of this variant. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available.
Still missing
- Tumor MSI/MMR IHC data would be required to evaluate PP4.
BA1 The variant is absent from gnomAD v4.1, not meeting the BA1 threshold of gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%). Details ▾Hide ▴
BS1 The variant is absent from gnomAD v4.1, not meeting the BS1 threshold of gnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%). Details ▾Hide ▴
BS2 No observation of this variant in trans with a known pathogenic MLH1 variant in a patient without CMMRD features has been reported. Details ▾Hide ▴
Evidence considered
- No co-occurrence in trans data available.
Still missing
- Clinical data on phase-confirmed co-occurrence would be needed.
BS3 No functional data demonstrating a benign effect for c.1177C>A (p.Leu393Ile) are available. The variant has not been tested in calibrated MMR functional assays. Details ▾Hide ▴
Evidence considered
- No variant-specific functional data indicating normal MMR function.
Still missing
- Calibrated functional assay data not available for this variant.
Sources
vcep_functional_assay_svi_documentation_mmroncokb ↗
BS4 No lack-of-segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Pedigree data would be required to assess BS4.
BP5 No tumor data demonstrating MSS status, retained MMR protein expression, or BRAF V600E/MLH1 methylation in carriers of this variant are available. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available.
Still missing
- Tumor MSS/MMR IHC/BRAF methylation data would be required to evaluate BP5.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (p.Leu393Ile) does not qualify for PVS1 under the InSiGHT MLH1 VCEP v2.0 framework, which restricts PVS1 to null variants (nonsense, frameshift, canonical splice, large deletions, or initiation codon variants). Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 393
- not a null variant type eligible for PVS1 under VCEP rules.
Sources
pvs1_variant_assessment
PS4 VCEPPS4 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
PM1 VCEPPM1 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
PM6 VCEPPM6 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
PP2 VCEPPP2 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
PP5 VCEPPP5 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
BP1 VCEPBP1 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
BP2 VCEPBP2 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
BP6 VCEPBP6 is designated Not Applicable by the InSiGHT MLH1 VCEP v2.0 per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
BP7 N/ABP7 under the InSiGHT VCEP is restricted to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. c.1177C>A is a missense substitution (p.Leu393Ile) and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous/intronic variants only per VCEP.
Sources
PS5 N/APS5 is not included in the InSiGHT MLH1 VCEP v2.0 criteria set. Details ▾Hide ▴
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.3
- Coding (HGVS c.)
- NM_000249.3:c.1177C>A
- Protein (HGVS p.)
- NP_000240.1:p.(Leu393Ile)
- GRCh38
- chr3:37025775 C>A
- GRCh37
- chr3:37067266 C>A
Gene diagram
Every interpreted variant in MLH1, mapped onto the exon structure of NM_000249.3. Select a row to find it on the plot.
MLH1NM_000249.3
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.415
- BayesDel
- -0.070
How the predictions were used
BP4 SupportingHCI prior probability for pathogenicity is 0.0225, meeting the InSiGHT VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors also suggest a benign or indeterminate effect: SpliceAI max delta 0.02 (no splicing impact), REVEL 0.415 (indeterminate), BayesDel -0.07 (indeterminate). Details ▾Hide ▴
Evidence considered
- HCI prior probability 0.0225 (<0.11 threshold for BP4_Supporting).
- SpliceAI max delta 0.02 (no predicted splice impact).
- REVEL 0.415
- BayesDel -0.07 (both indeterminate).
Sources
PP3 HCI prior probability for pathogenicity is 0.0225, well below the InSiGHT VCEP PP3 thresholds (>0.81 for moderate, >0.68 for supporting). SpliceAI predicts no splicing impact (max delta score 0.02, below the 0.2 threshold). REVEL score is 0.415 (indeterminate). Details ▾Hide ▴
Evidence considered
- HCI prior probability 0.0225 (below PP3 thresholds of >0.68/0.81).
- SpliceAI max delta 0.02 (no predicted splice impact).
- REVEL score 0.415 (indeterminate).
- BayesDel score -0.07 (indeterminate).
Sources
BP7 N/ABP7 under the InSiGHT VCEP is restricted to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. c.1177C>A is a missense substitution (p.Leu393Ile) and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous/intronic variants only per VCEP.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.415. BayesDel score = -0.0696399. HCI prior probability for pathogenicity = 0.0225. MAPP score = 5.83. Custom PP2 score = 0.335.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_000249.3%3Ac.1177C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37067266-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37025775-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-37025775-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.3%3Ac.1177…
- OncoKB ↗www.oncokb.org/gene/MLH1/L393I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH1+c.1177C%3EA
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.415. BayesDel score = -0.0696399. HCI prior probability for pathogenicity = 0.0225. MAPP score = 5.83. Custom PP2 score = 0.335.
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.