The MLH1 NM_000249.4:c.688G>C (p.Glu230Gln; p.E230Q) variant has been reported in ClinVar as a variant of uncertain significance with four clinical laboratory submissions.1 This variant is present at very low frequency in population databases, including gnomAD v4.1 at 2/1576948 alleles (AF 1.26827e-06; grpmax FAF 2.9e-07) and gnomAD v2.1 at 1/31410 alleles (AF 3.1837e-05), which is below the MLH1 PM2_Supporting threshold of 0.00002 in gnomAD v4.2 No variant-specific calibrated functional assay result for p.Glu230Gln was identified in the reviewed mismatch repair functional assay references.3 For this MLH1 missense variant, the HCI prior probability is 0.0581, below the BP4 threshold of 0.11; REVEL is 0.627, BayesDel is 0.158729, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.4
MLH1
Final classification
Uncertain Significance - Conflicting Evidence
MLH1 c.688G>C · p.Glu230Gln
MLH1
The MLH1 NM_000249.4:c.688G>C (p.Glu230Gln; p.E230Q) variant has been reported in ClinVar as a variant of uncertain significance with four clinical laboratory submissions.
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: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2
BP4
Uncertain Significance - Conflicting Evidence
MLH1 c.688G>C
PM2 + BP4
→
Uncertain Significance - Conflicting Evidence
3
vcep_functional_assay_svi_documentation_mmroncokb ↗
4
hci_priorrevelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_000249.4 · variants mapped to exon structure
MLH1
NM_000249.4
Fetching transcript structure from UCSC…
Applied criteria · 2 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= 1.26827e-06; MAF= 0.00013%, 2/1576948 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74471e-06; MAF= 0.00017%, 2/1146320 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.1837e-05; MAF= 0.00318%, 1/31410 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4792e-05; MAF= 0.00648%, 1/15434 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00013%
· 2 / 1,576,948
0 hom · FAF 2.9e-05%
0 hom · FAF 2.9e-05%
European (non-Finnish) 2 / 1,146,320 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0032%
· 1 / 31,410
0 hom
0 hom
European (non-Finnish) 1 / 15,434 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 483554)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.627. BayesDel score = 0.158729. HCI prior probability for pathogenicity = 0.0581. MAPP score = 4.41. Custom PP2 score = 0.715.
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
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.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR