0%
MLH1c.1990-23G>TNot classified
Print report
Variant interpretation report

MLH1 c.1990-23G>T, p.?

NM_000249.4:c.1990-23G>T NP_000240.1:p.? View identifiers
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.

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: 3
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

In gnomAD v4.1, this variant is present in 6 of 1,539,510 alleles with a total allele frequency of 0.00000389734, which is below the PM2_Supporting threshold of 0.00002. This supports PM2 at supporting strength.

Benign criteria applied · 3
BS1Strong
BS1 · strong

In gnomAD v4.1, the grpmax filtering allele frequency is 0.00013658, which is within the BS1 range of 0.0001 to less than 0.001. No evidence was identified that this variant is a known founder pathogenic variant, so BS1 is met.

BP4Supporting
BP4 · supporting

SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.00, which is below the BP4 threshold of 0.1. This supports BP4.

BP7Supporting
BP7 · supporting

This is an intronic variant at c.1990-23, which is beyond the BP7 distance threshold of -21 for 5′ intronic positions. This supports BP7.

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 final-classification framework: Rule24 (>=1 Benign Strong and >=1 Pathogenic Supporting) -> 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
6 / 1,539,510 alleles

gnomAD v4.1: 6 / 1,539,510 alleles. Recorded AF 3.89734e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.99023e-06; MAF= 0.00040%, 1/250612 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163881; MAF= 0.01639%, 1/6102 alleles, homozygotes = 0).

Applied · PM2, BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4, BP7 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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 ↗
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 v2.0.0, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 3 not met · 10 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PS3PM3PP5PP4PS1PP2PM5PS2PP1PVS1PM4PP3PM6PM1PS4PM2
Benign
BP6BA1BP3BP5BS1BP2BP4BP7BS2BP1BS4BS3
Met Not met Not assessed Not applicable

The MLH1 c.1990-23G>T (p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

In gnomAD v4.1, this variant is very rare overall at 6/1539510 alleles (AF 0.00000389734), which is below the MLH1 PM2_Supporting threshold of 0.00002, but the gnomAD v4.1 grpmax filtering allele frequency is 0.00013658 in the Middle Eastern population, which falls within the MLH1 BS1 range of 0.0001 to less than 0.001; gnomAD v2.1 also shows only 1/250612 alleles (AF 0.00000399023).

No variant-specific functional or constitutional RNA assay evidence was identified for this variant, so PS3 and BS3 were not assessed.

SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the BP4 threshold of 0.1 and below the PP3 threshold of 0.2, and the intronic position c.1990-23 is beyond the BP7 distance threshold of -21.

Met · 4

BS1 StrongIn gnomAD v4.1, the grpmax filtering allele frequency is 0.00013658, which is within the BS1 range of 0.0001 to less than 0.001. No evidence was identified that this variant is a known founder pathogenic variant, so BS1 is met. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.
Evidence considered
  • gnomAD v4.1 grpmax FAF = 0.00013658
  • ClinVar: no result found
  • No PMIDs identified
Still missing
  • Manual confirmation that no founder-pathogenic exception applies
Sources
evidence.json:results.gnomad.GNOMAD_V4_1evidence.json:results.clinvarliterature_pass.json
BP4 SupportingSpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.00, which is below the BP4 threshold of 0.1. This supports BP4. Details ▾Hide ▴
Rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1.
Evidence considered
  • SpliceAI max delta score = 0.00
Sources
evidence.json:results.spliceaiprefetch.json:steps.cspec.criteria[BP4]
BP7 SupportingThis is an intronic variant at c.1990-23, which is beyond the BP7 distance threshold of -21 for 5′ intronic positions. This supports BP7. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
  • Variant position = c.1990-23
Sources
case_summary.json:normalizationprefetch.json:steps.cspec.criteria[BP7]
PM2 SupportingIn gnomAD v4.1, this variant is present in 6 of 1,539,510 alleles with a total allele frequency of 0.00000389734, which is below the PM2_Supporting threshold of 0.00002. This supports PM2 at supporting strength. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.
Evidence considered
  • gnomAD v4.1 total AF = 3.897343960091198e-06
  • 6/1539510 alleles, homozygotes = 0
Sources
evidence.json:results.gnomad.GNOMAD_V4_1prefetch.json:steps.cspec.criteria[PM2]

Not met · 3 · evaluated, threshold not reached

BA1 The gnomAD v4.1 grpmax filtering allele frequency is 0.00013658, which is below the BA1 threshold of 0.001, so stand-alone benign population evidence is not met. Details ▾Hide ▴
Rule
GnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%) and variant is excluded as founder pathogenic variant.
Evidence considered
  • gnomAD v4.1 grpmax FAF = 0.00013658
Sources
evidence.json:results.gnomad.GNOMAD_V4_1
PVS1 This variant is a non-canonical intronic change at c.1990-23 rather than a canonical +/-1 or +/-2 splice-site variant, truncating variant, initiation codon variant, or exon-level deletion/duplication, and no RNA evidence of a loss-of-function splice defect was identified. Available evidence does not support PVS1. Details ▾Hide ▴
Rule
PVS1 applies to qualifying loss-of-function variants or confirmed splice defects under the MLH1 MMR specification.
Evidence considered
  • Variant = NM_000249.4:c.1990-23G>T
  • SpliceAI max delta score = 0.00
  • No variant-specific RNA study identified
Still missing
  • Variant-specific constitutional RNA studies if loss-of-function splicing remains clinically suspected
Sources
case_summary.json:normalizationevidence.json:results.spliceaiprefetch.json:steps.cspec.criteria[PVS1]
PP3 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00, which is below the PP3 threshold of 0.2 for a predicted splice defect. Available in silico evidence does not support PP3. Details ▾Hide ▴
Rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2.
Evidence considered
  • SpliceAI max delta score = 0.00
Sources
evidence.json:results.spliceaiprefetch.json:steps.cspec.criteria[PP3]

Not assessed · 10 · no assessment recorded

PS3 No variant-specific calibrated functional assay, RNA study, or monoallelic expression result was identified for this MLH1 intronic variant, so pathogenic functional evidence cannot be applied. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No variant-specific functional result was identified in the reviewed VCEP materials.
Still missing
  • Variant-specific functional assay data
  • Variant-specific constitutional RNA studies with NMD evaluation
Sources
literature_pass.jsonvcep_materials.jsonprefetch.json:steps.cspec.criteria[PS3]
PM3 No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic MLH1 variant in an individual with features consistent with constitutional mismatch repair deficiency, so PM3 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No qualifying CMMRD/trans observation was identified.
Still missing
  • Confirmed phase data
  • CMMRD phenotype data
  • Reported trans observations with another pathogenic MLH1 variant
Sources
literature_pass.jsonprefetch.json:steps.cspec.criteria[PM3]vcep_materials.json
PP4 No tumor microsatellite instability result, mismatch repair immunohistochemistry pattern, or MLH1 promoter methylation result was identified, so phenotype-specific tumor evidence for PP4 was not available. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No qualifying tumor phenotype data were identified.
Still missing
  • MSI testing
  • MMR IHC pattern
  • MLH1 promoter methylation testing
Sources
literature_pass.jsonprefetch.json:steps.cspec.criteria[PP4]
PS1 No previously established pathogenic or likely pathogenic variant affecting this same non-canonical splice nucleotide with similar or greater predicted splice impact was identified in the reviewed materials, so PS1 was not applied. Details ▾Hide ▴
Evidence considered
  • Reviewed VCEP pilot variant file did not identify this nucleotide position.
Still missing
  • Comprehensive confirmation of same-nucleotide pathogenic or likely pathogenic splice variants, if any
Sources
prefetch.json:steps.cspec.criteria[PS1]vcep_db/MLH1/files/VCEP-pilot-variants---MMR.xlsx
PS2 No confirmed de novo occurrence data were identified for this variant, so PS2 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No de novo evidence was identified.
Still missing
  • Proband phenotype information
  • Parental testing
  • Confirmed de novo documentation
Sources
literature_pass.jsonprefetch.json:steps.cspec.criteria[PS2]
PP1 No segregation data were identified, so co-segregation evidence for PP1 could not be assessed. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No segregation evidence was identified.
Still missing
  • Pedigree data
  • Affected and unaffected relative genotypes
  • Segregation likelihood ratio
Sources
literature_pass.jsonprefetch.json:steps.cspec.criteria[PP1]
BP5 No tumor data were identified showing microsatellite-stable disease, intact mismatch repair protein expression, inconsistent mismatch repair loss, or MLH1 methylation/BRAF V600E findings that would support BP5. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No qualifying benign tumor profile was identified.
Still missing
  • Tumor MSI status
  • Tumor IHC results
  • MLH1 methylation results
  • BRAF V600E results where relevant
Sources
literature_pass.jsonprefetch.json:steps.cspec.criteria[BP5]
BS2 No evidence was identified showing this variant in trans with a known pathogenic MLH1 variant in an older affected individual without features of constitutional mismatch repair deficiency, so BS2 could not be assessed. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No qualifying in-trans co-occurrence observation was identified.
Still missing
  • Confirmed phase data
  • Age-at-diagnosis data
  • Clinical assessment for CMMRD features
Sources
literature_pass.jsonprefetch.json:steps.cspec.criteria[BS2]vcep_materials.json
BS4 No informative lack-of-segregation data were identified, so BS4 could not be assessed. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No non-segregation evidence was identified.
Still missing
  • Pedigree data
  • Relative genotypes
  • Likelihood ratio for non-segregation
Sources
literature_pass.jsonprefetch.json:steps.cspec.criteria[BS4]
BS3 No variant-specific laboratory evidence showing normal mRNA splicing, no allelic imbalance, or proficient function was identified, so benign functional evidence could not be applied. Details ▾Hide ▴
Evidence considered
  • No PMIDs were identified.
  • No qualifying benign functional result was identified.
Still missing
  • Variant-specific constitutional RNA assay with NMD inhibition
  • Variant-specific functional assay showing proficient function
Sources
literature_pass.jsonvcep_materials.jsonprefetch.json:steps.cspec.criteria[BS3]
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
BP6 N/ABP6 is not used in the MLH1 InSiGHT hereditary colorectal cancer/polyposis specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists BP6 as not applicable.
Sources
case_summary.json:cspec.criteria[BP6]prefetch.json:steps.cspec.criteria[BP6]
PP5 N/APP5 is not used in the MLH1 InSiGHT hereditary colorectal cancer/polyposis specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists PP5 as not applicable.
Sources
case_summary.json:cspec.criteria[PP5]prefetch.json:steps.cspec.criteria[PP5]
PP2 N/APP2 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists PP2 as not applicable.
Sources
case_summary.json:cspec.criteria[PP2]prefetch.json:steps.cspec.criteria[PP2]
PM5 N/APM5 is a missense-residue rule and does not apply to this intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant is intronic: NM_000249.4:c.1990-23G>T; protein consequence is p.?.
Sources
case_summary.json:normalizationprefetch.json:steps.cspec.criteria[PM5]
BP3 N/ABP3 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists BP3 as not applicable.
Sources
case_summary.json:cspec.criteria[BP3]prefetch.json:steps.cspec.criteria[BP3]
BP2 N/ABP2 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists BP2 as not applicable.
Sources
case_summary.json:cspec.criteria[BP2]prefetch.json:steps.cspec.criteria[BP2]
PM4 N/APM4 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists PM4 as not applicable.
Sources
case_summary.json:cspec.criteria[PM4]prefetch.json:steps.cspec.criteria[PM4]
PM6 N/APM6 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists PM6 as not applicable.
Sources
case_summary.json:cspec.criteria[PM6]prefetch.json:steps.cspec.criteria[PM6]
PM1 N/APM1 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists PM1 as not applicable.
Sources
case_summary.json:cspec.criteria[PM1]prefetch.json:steps.cspec.criteria[PM1]
BP1 N/ABP1 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists BP1 as not applicable.
Sources
case_summary.json:cspec.criteria[BP1]prefetch.json:steps.cspec.criteria[BP1]
PS4 N/APS4 is not applicable for this MLH1 specification. Details ▾Hide ▴
Evidence considered
  • MLH1 InSiGHT VCEP specification v2.0.0 lists PS4 as not applicable.
Sources
case_summary.json:cspec.criteria[PS4]prefetch.json:steps.cspec.criteria[PS4]

Identifiers

Gene
MLH1
Transcript
NM_000249.4
Coding (HGVS c.)
NM_000249.4:c.1990-23G>T
Protein (HGVS p.)
NP_000240.1:p.?
GRCh38
chr3:37048881 G>T
GRCh37
chr3:37090372 G>T

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 6 / 1,539,510 alleles AF 3.9e-06 · 0 homozygotes · FAF 0.000137
gnomAD v2.1 1 / 250,612 alleles AF 3.99e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 3.9e-06 · 6 / 1,539,510 alleles · 0 hom · FAF 0.00014
Middle Eastern3 / 5,944 0.0005
Remaining individuals2 / 59,920 3.3e-05
Admixed American1 / 59,920 1.7e-05
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 4e-06 · 1 / 250,612 alleles · 0 hom
Remaining individuals1 / 6,102 0.00016
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.89734e-06; MAF= 0.00039%, 6/1539510 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000504711; MAF= 0.05047%, 3/5944 alleles, homozygotes = 0); grpmax FAF= 0.00013658.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.99023e-06; MAF= 0.00040%, 1/250612 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163881; MAF= 0.01639%, 1/6102 alleles, homozygotes = 0).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.00, which is below the BP4 threshold of 0.1. This supports BP4. Details ▾Hide ▴
Rule
For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1.
Evidence considered
  • SpliceAI max delta score = 0.00
Sources
evidence.json:results.spliceaiprefetch.json:steps.cspec.criteria[BP4]
BP7 SupportingThis is an intronic variant at c.1990-23, which is beyond the BP7 distance threshold of -21 for 5′ intronic positions. This supports BP7. Details ▾Hide ▴
Rule
A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.
Evidence considered
  • Variant position = c.1990-23
Sources
case_summary.json:normalizationprefetch.json:steps.cspec.criteria[BP7]
PP3 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00, which is below the PP3 threshold of 0.2 for a predicted splice defect. Available in silico evidence does not support PP3. Details ▾Hide ▴
Rule
Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2.
Evidence considered
  • SpliceAI max delta score = 0.00
Sources
evidence.json:results.spliceaiprefetch.json:steps.cspec.criteria[PP3]

Statement

In silico

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

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 6 / 1,539,510 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record
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

This variant is present in gnomAD v4.1 (AF= 3.89734e-06; MAF= 0.00039%, 6/1539510 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000504711; MAF= 0.05047%, 3/5944 alleles, homozygotes = 0); grpmax FAF= 0.00013658.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.99023e-06; MAF= 0.00040%, 1/250612 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163881; MAF= 0.01639%, 1/6102 alleles, homozygotes = 0).

ClinVar

This variant is absent from ClinVar.

In silico

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

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).