The MLH1 c.1990-23G>T (p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.1 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).2 No variant-specific functional or constitutional RNA assay evidence was identified for this variant, so PS3 and BS3 were not assessed.3 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 -21.4
Final classification
Uncertain Significance - Conflicting Evidence
PM2BS1BP4BP7
MLH1
c.1990-23G>T
p.?
This variant
The MLH1 c.1990-23G>T (p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
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.
Classification rationale
PM2
BS1BP4BP7
Uncertain Significance - Conflicting Evidence
MLH1 c.1990-23G>T
PM2 + BS1 + BP4 + BP7
→
Uncertain Significance - Conflicting Evidence
1
evidence.json:results.cosmicevidence.json:results.clinvar
2
evidence.json:results.gnomad.GNOMAD_V4_1evidence.json:results.gnomad.GNOMAD_V2_1
3
literature_pass.jsonvcep_materials.json
4
evidence.json:results.spliceaicase_summary.json:normalization
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.
Gene diagram
· NM_000249.4 · variants mapped to exon structure
MLH1
NM_000249.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
BS1
Strong
review
Benign
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.
gnomAD v4.1 grpmax FAF = 0.00013658ClinVar: no result foundNo PMIDs identified
BP4
Supporting
review
Benign
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.
SpliceAI max delta score = 0.00
BP7
Supporting
review
Benign
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.
Variant position = c.1990-23
PM2
Supporting
review
Pathogenic
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.
gnomAD v4.1 total AF = 3.897343960091198e-066/1539510 alleles, homozygotes = 0
Assessed · not applied
· 3 not met · 10 not assessed
Pathogenic
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.
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.
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.
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.
PS2
No confirmed de novo occurrence data were identified for this variant, so PS2 cannot be assessed.
PP1
No segregation data were identified, so co-segregation evidence for PP1 could not be assessed.
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.
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.
Benign
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.
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.
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.
BS4
No informative lack-of-segregation data were identified, so BS4 could not be assessed.
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.
N/A · 11
BP6 · PP5 · PP2 · PM5 · BP3 · BP2 · PM4 · PM6 · PM1 · BP1 · PS4
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00039%
· 6 / 1,539,510
0 hom · FAF 0.014%
0 hom · FAF 0.014%
Middle Eastern 3 / 5,944 |
0.05% |
Remaining individuals 2 / 59,920 |
0.0033% |
Admixed American 1 / 59,920 |
0.0017% |
+ 7 not observed (European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0004%
· 1 / 250,612
0 hom
0 hom
Remaining individuals 1 / 6,102 |
0.016% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links