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
MLH1
Final classification
Uncertain Significance - Conflicting Evidence
MLH1 c.1990-23G>T · p.?
MLH1
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
Gene diagram
· NM_000249.4 · variants mapped to exon structure
MLH1
NM_000249.4
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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