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LYFE SCIENCES
Project: HERA
NM_001040108.2:c.3488G>A
p.Gly1163Asp  ·  MLH3
ACMG/AMP
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Classification rationale
1

The MLH3 c.3488G>A (p.Gly1163Asp; p.G1163D) variant has been reported in ClinVar, where most submissions classify it as benign (6 laboratories) and a minority classify it as uncertain significance (2 laboratories).

clinvar ↗
2

This variant is common in population databases, with East Asian allele frequencies of 2.83720% in gnomAD v2.1 and 2.24070% in gnomAD v4.1, exceeding the default BA1 threshold of 1% and BS1 threshold of 0.3%.

gnomad_v2 ↗ gnomad_v4 ↗
3

Computational evidence argues against a deleterious effect: SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.113, and BayesDel is -0.258625.

spliceai ↗
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
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Gaps remaining
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Rule
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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= 0.00212908; MAF= 0.21291%, 600/281812 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.028372; MAF= 2.83720%, 565/19914 alleles, homozygotes = 3); grpmax FAF= 0.0263843.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000720685; MAF= 0.07207%, 1147/1591542 alleles, homozygotes = 9) and has highest observed frequency in the East Asian population (AF= 0.022407; MAF= 2.24070%, 989/44138 alleles, homozygotes = 7); grpmax FAF= 0.0212477.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories).
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. MLH3, a DNA mismatch repair protein, is infrequently altered in cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.113. BayesDel score = -0.258625.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105867929, n = 2 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueG1163
Hotspots ↗