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LYFE SCIENCES
Project: HERA
NM_000249.4:c.688G>C
p.Glu230Gln  ·  MLH1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

No variant-specific calibrated functional assay result for p.Glu230Gln was identified in the reviewed mismatch repair functional assay references.

oncokb ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 483554)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
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.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE230
Hotspots ↗