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MLH1c.342_347delUncertain significance
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Variant interpretation report

MLH1 c.342_347del, p.(Ile115_Thr116del)

NM_000249.4:c.342_347del NP_000240.1:p.(Ile115_Thr116del) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MLH1

No gene-level summary was recorded for this case.

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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000249.4:c.342_347del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the InSiGHT MLH1 VCEP PM2_Supporting threshold (allele frequency <0.00002 in gnomAD v4).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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 was evaluated deterministically with applied criteria: PM2 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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
COSMIC ↗Cancer Hotspots ↗
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: 1 met · 3 not met · 8 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000249.4:c.342_347del (p.Ile115_Thr116del) is an in-frame deletion in exon 4 of MLH1. It is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2_Supporting under the InSiGHT MLH1 VCEP framework.

Under the InSiGHT MLH1 VCEP v2.0.0, PVS1 is not applicable because this in-frame deletion does not introduce a premature termination codon and does not meet the VCEP criteria for nonsense, frameshift, or canonical splice variants.

No functional studies, tumor phenotype data, segregation data, or de novo observations were identified for this variant in any reviewed publication or database. Six papers were reviewed in full text; none mention NM_000249.4:c.342_347del.

This variant has been reported in ClinVar as Uncertain Significance (1 clinical laboratory, criteria provided, single submitter). Under the InSiGHT MLH1 VCEP framework, PP5 is not applicable and this single submission does not constitute independent evidence for classification.

With PM2_Supporting as the only met criterion and no benign criteria met, this variant remains a Variant of Uncertain Significance under the InSiGHT MLH1 VCEP classification rules. All other applicable criteria are either not met, not applicable by VCEP designation, or cannot be assessed due to absence of data.

Met · 1

PM2 SupportingNM_000249.4:c.342_347del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the InSiGHT MLH1 VCEP PM2_Supporting threshold (allele frequency <0.00002 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
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Not met · 3 · evaluated, threshold not reached

PVS1 NM_000249.4:c.342_347del is an in-frame deletion of 6 nucleotides removing Ile115 and Thr116 (p.Ile115_Thr116del). It does not introduce a premature termination codon and is not a canonical splice variant; therefore it does not satisfy the InSiGHT MLH1 VCEP PVS1 criteria, which require nonsense, frameshift, or canonical splice variants introducing a PTC at or before codon 753. Details ▾Hide ▴
Evidence considered
  • Variant is an in-frame deletion (c.342_347del) removing 6 nucleotides in exon 4
  • preserving the reading frame
  • InSiGHT MLH1 VCEP PVS1 criteria apply only to nonsense
  • frameshift
  • and canonical splice variants introducing a PTC
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessment
BA1 NM_000249.4:c.342_347del is absent from gnomAD v4.1; the InSiGHT MLH1 VCEP BA1 threshold requires a gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%), which is not met. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v4.1
  • does not meet >=0.1% AF threshold
Sources
gnomad_v4 ↗cspec ↗
BS1 NM_000249.4:c.342_347del is absent from gnomAD v4.1; the InSiGHT MLH1 VCEP BS1 threshold requires a gnomAD v4 Grpmax filtering allele frequency >= 0.0001 (0.01%), which is not met. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v4.1
  • does not meet >=0.01% AF threshold
Sources
gnomad_v4 ↗cspec ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo observation data have been reported for NM_000249.4:c.342_347del in the available evidence. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar
  • literature
  • or evidence sources
Still missing
  • De novo testing data for this variant
PS3 No variant-specific functional studies or calibrated functional assay data were identified for NM_000249.4:c.342_347del in the literature or InSiGHT VCEP functional assay documentation. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect with no variant-specific functional data
  • No calibrated functional assay result for this variant in the VCEP MMR functional assay documentation
  • No functional studies mentioning this variant found in any of the 6 full-text papers reviewed
Still missing
  • Functional assay data for p.Ile115_Thr116del
Sources
vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data are available for NM_000249.4:c.342_347del in any reported pedigrees. Details ▾Hide ▴
Evidence considered
  • No co-segregation reports identified in literature or ClinVar
Still missing
  • Co-segregation data from affected families
PP4 No tumor MSI or MMR immunohistochemistry data have been reported for patients carrying NM_000249.4:c.342_347del. Details ▾Hide ▴
Evidence considered
  • No tumor phenotype data available in ClinVar
  • literature
  • or evidence sources
Still missing
  • Tumor MSI status and MMR IHC for patients harboring this variant
BS2 No data are available regarding co-occurrence in trans with a known pathogenic MLH1 variant in a patient with colorectal or Lynch syndrome spectrum cancer after age 45 without CMMRD features. Details ▾Hide ▴
Evidence considered
  • No trans co-occurrence data identified
Still missing
  • Co-occurrence in trans data
BS3 No variant-specific functional studies demonstrating normal MMR function have been identified for NM_000249.4:c.342_347del in the literature or InSiGHT VCEP calibrated functional assay documentation. Details ▾Hide ▴
Evidence considered
  • No calibrated functional assay result for this variant
  • No functional studies demonstrating normal function identified in any reviewed paper
Still missing
  • Functional assay data demonstrating proficient MMR function
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No segregation data are available to evaluate lack of co-segregation with disease for NM_000249.4:c.342_347del. Details ▾Hide ▴
Evidence considered
  • No segregation or lack-of-segregation reports identified
Still missing
  • Segregation data from affected families
BP5 No tumor phenotype data (MSS status, MMR IHC, BRAF V600E, or MLH1 promoter methylation) are available for patients carrying NM_000249.4:c.342_347del. Details ▾Hide ▴
Evidence considered
  • No tumor data available for this variant
Still missing
  • Tumor MSS/MSI status
  • MMR IHC
  • BRAF
  • and MLH1 methylation data
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AInSiGHT MLH1 VCEP PS1 applies only to missense substitutions encoding the same amino acid change or splice variants affecting the same non-canonical splice nucleotide; this in-frame deletion does not qualify. Details ▾Hide ▴
Evidence considered
  • VCEP PS1 rule is restricted to missense and splice variants
Sources
cspec ↗
PS4 VCEPInSiGHT MLH1 VCEP PS4 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP PS4: Not Applicable
Sources
cspec ↗
PM1 VCEPInSiGHT MLH1 VCEP PM1 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP PM1: Not Applicable
Sources
cspec ↗
PM4 VCEPInSiGHT MLH1 VCEP PM4 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP PM4: Not Applicable
Sources
cspec ↗
PM5 N/AInSiGHT MLH1 VCEP PM5 applies only to missense changes at an amino acid residue where a different missense change was classified as Pathogenic or Likely Pathogenic; this variant is an in-frame deletion, not a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant class is in-frame deletion
  • not missense
  • not eligible for classic same-residue PM5
Sources
cspec ↗pm5_candidates
PM6 VCEPInSiGHT MLH1 VCEP PM6 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP PM6: Not Applicable
Sources
cspec ↗
PP2 VCEPInSiGHT MLH1 VCEP PP2 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP PP2: Not Applicable
Sources
cspec ↗
PP3 N/AInSiGHT MLH1 VCEP PP3 applies only to missense variants with HCI prior scores or splice predictions for non-canonical splice sites. This is an in-frame coding deletion with no HCI prior available and a SpliceAI max delta score of 0.00; neither PP3 rule applies. Details ▾Hide ▴
Evidence considered
  • HCI prior not applicable to in-frame deletions
  • SpliceAI max delta score = 0.00
  • predicting no splice impact
Sources
cspec ↗spliceai ↗
PP5 VCEPInSiGHT MLH1 VCEP PP5 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP PP5: Not Applicable
Sources
cspec ↗
BP1 VCEPInSiGHT MLH1 VCEP BP1 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP BP1: Not Applicable
Sources
cspec ↗
BP2 VCEPInSiGHT MLH1 VCEP BP2 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP BP2: Not Applicable
Sources
cspec ↗
BP3 VCEPInSiGHT MLH1 VCEP BP3 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP BP3: Not Applicable
Sources
cspec ↗
BP4 N/AInSiGHT MLH1 VCEP BP4 applies only to missense variants with HCI prior <0.11 or intronic/synonymous variants with SpliceAI delta <= 0.1. This is an in-frame coding deletion; neither BP4 rule applies. Details ▾Hide ▴
Evidence considered
  • HCI prior not applicable to in-frame deletions
  • SpliceAI max delta = 0.00 but BP4 splice rule applies only to intronic/synonymous variants
Sources
cspec ↗spliceai ↗
BP6 VCEPInSiGHT MLH1 VCEP BP6 is designated Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP BP6: Not Applicable
Sources
cspec ↗
BP7 N/AInSiGHT MLH1 VCEP BP7 applies only to synonymous or intronic variants at or beyond -21/+7; this is an in-frame coding deletion and does not qualify. Details ▾Hide ▴
Evidence considered
  • VCEP BP7 restricted to synonymous and intronic variants
Sources
cspec ↗
PS5 N/APS5 is not included in the InSiGHT MLH1 VCEP criteria; its supporting-strength counterpart PP5 is also explicitly designated Not Applicable by this VCEP. Details ▾Hide ▴
Evidence considered
  • PS5 not present in VCEP criteria
  • PP5 designated Not Applicable
Sources
cspec ↗

Identifiers

Gene
MLH1
Transcript
NM_000249.4
Coding (HGVS c.)
NM_000249.4:c.342_347del
Protein (HGVS p.)
NP_000240.1:p.(Ile115_Thr116del)
GRCh38
chr3:37004431 GTTACTA>G
GRCh37
chr3:37045922 GTTACTA>G
ClinVar
4081840

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…
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

Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/AInSiGHT MLH1 VCEP PP3 applies only to missense variants with HCI prior scores or splice predictions for non-canonical splice sites. This is an in-frame coding deletion with no HCI prior available and a SpliceAI max delta score of 0.00; neither PP3 rule applies. Details ▾Hide ▴
Evidence considered
  • HCI prior not applicable to in-frame deletions
  • SpliceAI max delta score = 0.00
  • predicting no splice impact
Sources
cspec ↗spliceai ↗
BP4 N/AInSiGHT MLH1 VCEP BP4 applies only to missense variants with HCI prior <0.11 or intronic/synonymous variants with SpliceAI delta <= 0.1. This is an in-frame coding deletion; neither BP4 rule applies. Details ▾Hide ▴
Evidence considered
  • HCI prior not applicable to in-frame deletions
  • SpliceAI max delta = 0.00 but BP4 splice rule applies only to intronic/synonymous variants
Sources
cspec ↗spliceai ↗
BP7 N/AInSiGHT MLH1 VCEP BP7 applies only to synonymous or intronic variants at or beyond -21/+7; this is an in-frame coding deletion and does not qualify. Details ▾Hide ▴
Evidence considered
  • VCEP BP7 restricted to synonymous and intronic variants
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

6 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

  • NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.
    Febbo PG et al. · 2011
    NCCN Task Force report evaluating the clinical utility of tumor markers in oncology. NM_000249.4:c.342_347del was not identified in this paper.
    Does not name this variant
    PMID 22138009 ↗
  • Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.
    Duffy MJ et al. · 2014
    European Group on Tumor Markers 2014 guidelines update for tumor markers in colorectal, gastric, and gastrointestinal stromal cancers. NM_000249.4:c.342_347del was not identified in this paper.
    Does not name this variant
    PMID 23852704 ↗
  • 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.
    ACMG/AMP 2015 standards and guidelines for the interpretation of sequence variants. This is a methods guideline, not a variant-specific study. NM_000249.4:c.342_347del was not identified in this paper.
    Does not name this variant
    PMID 25741868 ↗
  • Lynch Syndrome.
    Adam MP et al. · 1993
    GeneReviews entry for Lynch Syndrome. NM_000249.4:c.342_347del was not identified in the abstract or available metadata for this entry. This is a general gene-level review, not a variant-specific report.
    Does not name this variant
    PMID 20301390 ↗
  • Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.
    García-Alfonso P et al. · 2015
    Updated Spanish consensus guidelines for biomarker testing in colorectal carcinoma. NM_000249.4:c.342_347del was not identified in this paper.
    Does not name this variant
    PMID 25373533 ↗
  • Update of the recommendations for the determination of biomarkers in colorectal carcinoma: National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology.
    2020 update of Spanish SEOM/SEAP recommendations for biomarker determination in colorectal carcinoma. NM_000249.4:c.342_347del was not identified in this paper.
    Does not name this variant
    PMID 32418154 ↗

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 0.000 Open source ↗
ClinVar 1 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

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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4081840)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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.