About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.1039-25T>A, p.?
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
Under the MLH1 VCEP, BA1 (Stand Alone) applies when the gnomAD v4 grpmax filtering allele frequency is ≥ 0.001 (0.1%) and the variant is excluded as a founder pathogenic variant. The gnomAD v4.1 joint grpmax FAF is 0.00157 (0.157%), which exceeds the 0.1% threshold. The variant is observed across multiple continental populations (AFR 0.194%, AMR 0.017%, ASJ 0.039%) with no evidence of a founder effect. The ClinVar classification of Likely benign from clinical laboratories is consistent with this being a common polymorphism.
BP4Supporting
BP4 · supporting
Under the MLH1 VCEP, BP4_Supporting applies to intronic variants when SpliceAI predicts no splicing impact with a delta score ≤ 0.1 (Walker et al. 2023). SpliceAI analysis of NM_000249.4:c.1039-25T>A yields a maximum delta score of 0.03, indicating no predicted effect on splicing. This criterion is independent of BP7 and both may be applied.
BP7Supporting
BP7 · supporting
Under the MLH1 VCEP, BP7_Supporting applies to intronic variants at or beyond -21/+7 of the exon boundary. NM_000249.4:c.1039-25T>A is located at position -25 relative to exon 11, which is beyond the -21 threshold. SpliceAI also predicts no splicing impact (delta 0.03). Per VCEP guidance, variants may satisfy both BP7 and BP4.
Recorded classification: Benign
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 Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP4 supporting, BP7 supporting; maps to Benign.
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
159 / 721,850 alleles
gnomAD v4.1: 159 / 721,850 alleles. Recorded AF 0.000220267. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000921359; MAF= 0.09214%, 34/36902 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00301887; MAF= 0.30189%, 16/5300 alleles, homozygotes = 0); grpmax FAF= 0.00198078.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00040830611292580493, 7/17144 alleles, homozygotes = 0).
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
No screenshot for this evidence
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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: 3 met · 13 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000249.4:c.1039-25T>A is an intronic variant located 25 bases upstream of exon 11 in MLH1.
This variant is present in gnomAD v4.1 with a joint grpmax filtering allele frequency of 0.157% (159/721,850 alleles), exceeding the InSiGHT MLH1 VCEP BA1 stand-alone benign threshold of 0.1%.
The variant is observed across multiple continental populations with highest frequency in the African/African American population (0.194%), consistent with a common polymorphism rather than a founder pathogenic variant.
SpliceAI predicts no splicing impact (max delta score 0.03), supporting application of BP4 (Supporting) for an intronic variant with no predicted splice defect.
The variant's intronic position at -25 relative to exon 11 satisfies BP7 (Supporting) under the VCEP rule for variants at or beyond the -21/+7 boundary.
The variant has been reported in ClinVar as Likely benign by two clinical laboratories (ClinVar Variation ID 492685), consistent with the population frequency data.
No criteria match.
Met · 3
BA1 Stand aloneUnder the MLH1 VCEP, BA1 (Stand Alone) applies when the gnomAD v4 grpmax filtering allele frequency is ≥ 0.001 (0.1%) and the variant is excluded as a founder pathogenic variant. The gnomAD v4.1 joint grpmax FAF is 0.00157 (0.157%), which exceeds the 0.1% threshold. The variant is observed across multiple continental populations (AFR 0.194%, AMR 0.017%, ASJ 0.039%) with no evidence of a founder effect. The ClinVar classification of Likely benign from clinical laboratories is consistent with this being a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 joint grpmax FAF 0.00157 (0.157%) ≥ VCEP BA1 threshold of 0.001
- Observed in multiple populations: AFR (69/35
- 582
- 0.194%)
- AMR (3/17
- 440
- 0.017%)
- ASJ (3/7
- 702
- 0.039%)
- No homozygotes in gnomAD (consistent with population frequency
- not suggestive of founder effect)
- Absent from East Asian populations
- ClinVar Likely benign
- consistent with a common benign polymorphism
Sources
BP4 SupportingUnder the MLH1 VCEP, BP4_Supporting applies to intronic variants when SpliceAI predicts no splicing impact with a delta score ≤ 0.1 (Walker et al. 2023). SpliceAI analysis of NM_000249.4:c.1039-25T>A yields a maximum delta score of 0.03, indicating no predicted effect on splicing. This criterion is independent of BP7 and both may be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.03 ≤ 0.1 — predicts no splicing impact
- VCEP BP4 rule for intronic variants: SpliceAI delta ≤ 0.1
Sources
BP7 SupportingUnder the MLH1 VCEP, BP7_Supporting applies to intronic variants at or beyond -21/+7 of the exon boundary. NM_000249.4:c.1039-25T>A is located at position -25 relative to exon 11, which is beyond the -21 threshold. SpliceAI also predicts no splicing impact (delta 0.03). Per VCEP guidance, variants may satisfy both BP7 and BP4. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.1039-25 (position -25)
- beyond the -21 threshold
- SpliceAI delta 0.03 — no predicted splicing impact
Sources
Not met · 13 · evaluated, threshold not reached
PVS1 NM_000249.4:c.1039-25T>A is a deep intronic variant located 25 bases upstream of exon 11. It does not affect a canonical splice donor/acceptor site (IVS±1,2). SpliceAI predicts no splicing impact (max delta score 0.03). Under the InSiGHT MLH1 VCEP v2.0, PVS1 is restricted to nonsense/frameshift variants introducing PTC at or before codon 753, large genomic alterations, IVS±1 or ±2 variants, mRNA-confirmed splicing aberrations, or initiation codon variants. This variant does not fall into any of these categories. Details ▾Hide ▴
Evidence considered
- Deep intronic variant (c.1039-25T>A)
- 25 bp upstream of exon 11
- SpliceAI max delta 0.03 — no predicted splicing impact
- Not at canonical splice consensus (±1
- 2)
Sources
PS1 PS1 under the MLH1 VCEP requires either (a) a missense substitution encoding the same amino acid change as a VCEP-classified Pathogenic variant, or (b) a variant affecting the same non-canonical splice nucleotide as a confirmed Pathogenic splice variant with similar or worse SpliceAI prediction. This intronic variant encodes no amino acid change and SpliceAI delta is only 0.03 (no predicted splicing defect), so neither condition applies. Details ▾Hide ▴
Evidence considered
- Intronic variant — no amino acid change
- SpliceAI delta 0.03 — no predicted splicing impact
- No known pathogenic variant at the same non-canonical splice nucleotide
Sources
PS2 No de novo occurrence data are available for NM_000249.4:c.1039-25T>A. The MLH1 VCEP PS2 criterion requires documented de novo events with confirmed maternity and paternity. No publications or ClinVar submissions report de novo observations for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature
Still missing
- No de novo data available
Sources
PS3 No functional data are available for NM_000249.4:c.1039-25T>A. The MLH1 VCEP PS3 criterion requires calibrated functional assay data with functional odds for pathogenicity, MMR function defect per the functional assay flowchart, or monoallelic expression data. No such evidence was identified in the InSiGHT functional assay SVI documentation, VCEP pilot variant spreadsheet, ClinVar, or published literature. Details ▾Hide ▴
Evidence considered
- Variant not listed in VCEP Functional-assay-SVI-documentation-MMR.xlsx
- Variant not listed in VCEP-pilot-variants---MMR.xlsx
- No functional studies identified in published literature
Still missing
- No functional assay data available
Sources
PM2 Under the MLH1 VCEP, PM2_Supporting requires an allele frequency < 0.00002 (< 1 in 50,000 alleles) in gnomAD v4. This variant is present in gnomAD v4.1 at an overall AF of 0.00022 (159/721,850 alleles; 0.022%), which exceeds the PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 159/721
- 850 alleles (AF 0.00022
- 0.022%)
- gnomAD v4.1 joint grpmax FAF 0.00157 (0.157%)
Sources
PP1 No co-segregation data are available for NM_000249.4:c.1039-25T>A. The MLH1 VCEP PP1 criterion requires co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio exceeding specified thresholds. No such data were identified in ClinVar or published literature. Details ▾Hide ▴
Evidence considered
- No co-segregation data available
Still missing
- No pedigree or co-segregation data
Sources
PP3 Under the MLH1 VCEP, PP3 for non-canonical splice variants requires a SpliceAI delta score ≥ 0.2 (Supporting) or an HCI prior probability > 0.68 (missense variants only). SpliceAI predicts no splicing impact (max delta 0.03), well below the VCEP threshold. The variant is intronic and has no HCI prior score. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.03 — below VCEP PP3 threshold (≥ 0.2)
- HCI prior not applicable (intronic variant
- no entry in HCI-PRIORS-MLH1.txt)
Sources
PP4 No tumor phenotype data (MSI status, IHC for MMR proteins) are available for carriers of NM_000249.4:c.1039-25T>A. The MLH1 VCEP PP4 criterion requires MSI-H CRC/endometrial tumors with MMR protein expression loss consistent with the variant location. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available
Still missing
- No MSI or IHC data for carriers of this variant
BS1 The MLH1 VCEP BS1 threshold is gnomAD v4 grpmax FAF ≥ 0.0001 and < 0.001. The observed grpmax FAF of 0.00157 exceeds the upper bound of the BS1 range and instead meets the higher BA1 threshold. BS1 is superseded by BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF 0.00157 > BS1 upper bound of 0.001
Sources
BS2 No co-occurrence data are available for NM_000249.4:c.1039-25T>A. The MLH1 VCEP BS2 criterion requires observation in trans with a known pathogenic variant in a patient with colorectal cancer after age 45 without CMMRD features, with confirmed phase. Details ▾Hide ▴
Evidence considered
- No co-occurrence data available
Still missing
- No co-occurrence or phase data
BS3 No functional data demonstrating a benign effect are available for NM_000249.4:c.1039-25T>A. The MLH1 VCEP BS3 criterion requires calibrated functional assays with odds for pathogenicity ≤ 0.48, or mRNA assays showing no splicing aberration or allelic imbalance with NMD inhibition. SpliceAI predicts no splicing impact (delta 0.03), but this in silico prediction alone does not satisfy the VCEP BS3 requirement for laboratory-based functional evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.03 — in silico only
- not laboratory assay
- No calibrated functional assay data available
Still missing
- No laboratory-based mRNA or protein functional data
Sources
BS4 No lack-of-segregation data are available for NM_000249.4:c.1039-25T>A. The MLH1 VCEP BS4 criterion requires a combined Bayes Likelihood Ratio < 0.48 from pedigrees showing absence of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No pedigree or segregation data available
Still missing
- No segregation data
BP5 No tumor phenotype data are available for evaluation under BP5. The MLH1 VCEP BP5 criterion requires CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in MSI-H tumors. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available
Still missing
- No MSI
- IHC
- or tumor methylation data
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPPS4 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
Sources
PM5 N/APM5 applies only to missense variants with a different missense change at the same amino acid residue classified as Pathogenic or Likely Pathogenic by the VCEP. NM_000249.4:c.1039-25T>A is an intronic variant with no protein consequence. Details ▾Hide ▴
PM6 VCEPPM6 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0 (missense variant in a gene with low rate of benign missense changes does not apply). Details ▾Hide ▴
Sources
PP5 VCEPPP5 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0. ClinVar review status is 'criteria provided, single submitter' (1-star), so the global PP5-at-supporting override for 3-star expert panel submissions does not apply. Details ▾Hide ▴
BP1 VCEPBP1 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0. Details ▾Hide ▴
Sources
BP6 VCEPBP6 is listed as Not Applicable by the InSiGHT MLH1 VCEP v2.0. ClinVar review status is 'criteria provided, single submitter' (1-star), so the global BP6-at-supporting override for 3-star expert panel submissions does not apply. Details ▾Hide ▴
PS5 N/APS5 is not recognized as a standalone criterion in the ACMG/AMP 2015 framework; the evidence type it represents is subsumed by PS1 and PM5. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.4
- Coding (HGVS c.)
- NM_000249.4:c.1039-25T>A
- Protein (HGVS p.)
- NP_000240.1:p.?
- GRCh38
- chr3:37025612 T>A
- GRCh37
- chr3:37067103 T>A
- ClinVar
- 492685
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
159 / 721,850 alleles
AF 0.00022 · 0 homozygotes · FAF 0.00157
gnomAD v2.1
34 / 36,902 alleles
AF 0.000921 · 0 homozygotes · FAF 0.00198
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00022 · 159 / 721,850 alleles · 0 hom · FAF 0.0016
| African/African American69 / 35,582 | 0.0019 |
| South Asian28 / 22,538 | 0.0012 |
| Ashkenazi Jewish4 / 10,280 | 0.00039 |
| Admixed American3 / 17,440 | 0.00017 |
| Remaining individuals3 / 24,634 | 0.00012 |
| East Asian2 / 18,806 | 0.00011 |
| European (non-Finnish)49 / 573,780 | 8.5e-05 |
| European (Finnish)1 / 16,150 | 6.2e-05 |
0 alternate alleles recorded in 2 other groups: Amish, Middle Eastern.
gnomAD v2.1
AF 0.00092 · 34 / 36,902 alleles · 0 hom · FAF 0.002
| African/African American16 / 5,300 | 0.003 |
| Admixed American2 / 1,248 | 0.0016 |
| Ashkenazi Jewish2 / 1,624 | 0.0012 |
| South Asian5 / 4,298 | 0.0012 |
| European (non-Finnish)8 / 18,924 | 0.00042 |
| European (Finnish)1 / 2,462 | 0.00041 |
0 alternate alleles recorded in 2 other groups: East Asian, Remaining individuals.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000220267; MAF= 0.02203%, 159/721850 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00193918; MAF= 0.19392%, 69/35582 alleles, homozygotes = 0); grpmax FAF= 0.00157149.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000921359; MAF= 0.09214%, 34/36902 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00301887; MAF= 0.30189%, 16/5300 alleles, homozygotes = 0); grpmax FAF= 0.00198078.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00040830611292580493, 7/17144 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingUnder the MLH1 VCEP, BP4_Supporting applies to intronic variants when SpliceAI predicts no splicing impact with a delta score ≤ 0.1 (Walker et al. 2023). SpliceAI analysis of NM_000249.4:c.1039-25T>A yields a maximum delta score of 0.03, indicating no predicted effect on splicing. This criterion is independent of BP7 and both may be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.03 ≤ 0.1 — predicts no splicing impact
- VCEP BP4 rule for intronic variants: SpliceAI delta ≤ 0.1
Sources
BP7 SupportingUnder the MLH1 VCEP, BP7_Supporting applies to intronic variants at or beyond -21/+7 of the exon boundary. NM_000249.4:c.1039-25T>A is located at position -25 relative to exon 11, which is beyond the -21 threshold. SpliceAI also predicts no splicing impact (delta 0.03). Per VCEP guidance, variants may satisfy both BP7 and BP4. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.1039-25 (position -25)
- beyond the -21 threshold
- SpliceAI delta 0.03 — no predicted splicing impact
Sources
PP3 Under the MLH1 VCEP, PP3 for non-canonical splice variants requires a SpliceAI delta score ≥ 0.2 (Supporting) or an HCI prior probability > 0.68 (missense variants only). SpliceAI predicts no splicing impact (max delta 0.03), well below the VCEP threshold. The variant is intronic and has no HCI prior score. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.03 — below VCEP PP3 threshold (≥ 0.2)
- HCI prior not applicable (intronic variant
- no entry in HCI-PRIORS-MLH1.txt)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
1 paper record 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
-
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. · 2015This is the ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. It describes the通用 framework for classifying variants using criteria such as PVS1, PS1-PS4, PM1-PM6, PP1-PP5, BA1, BS1-BS4, and BP1-BP7. The paper does not mention or evaluate NM_000249.4:c.1039-25T>A or any specific MLH1 intronic variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
159 / 721,850 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
2 Likely benign
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/492685/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37067103-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37025612-T-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-37025612-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.4%3Ac.1039…
- OncoKB ↗www.oncokb.org/gene/MLH1/?
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= 0.000220267; MAF= 0.02203%, 159/721850 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00193918; MAF= 0.19392%, 69/35582 alleles, homozygotes = 0); grpmax FAF= 0.00157149.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000921359; MAF= 0.09214%, 34/36902 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00301887; MAF= 0.30189%, 16/5300 alleles, homozygotes = 0); grpmax FAF= 0.00198078.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00040830611292580493, 7/17144 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 492685)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).