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MLH3
Final classification
Benign
MLH3 c.3488G>A · p.Gly1163Asp
MLH3

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).

Gene
MLH3
Transcript
NM_001040108.2
HGVS · transcript:coding
NM_001040108.2:c.3488G>A
Consequence
N/A
GRCh38
chr14:75039993 C>T
GRCh37
chr14:75506696 C>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign. ▾
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BP4 Benign
MLH3 c.3488G>A

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).1 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%.2 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 -0.258625.3

BA1 + BS1 + BP4 → Benign
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 spliceai ↗revelbayesdel
Gene diagram · NM_001040108.2 · variants mapped to exon structure
MLH3 NM_001040108.2
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This 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.
      v2.1
      This 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.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.072% · 1147 / 1,591,542
      9 hom · FAF 2.1%
      East Asian
      989 / 44,138
      2.2%
      7 hom
      Remaining individuals
      84 / 61,558
      0.14%
      2 hom
      African/African American
      38 / 74,270
      0.051%
      Admixed American
      23 / 59,712
      0.039%
      South Asian
      5 / 90,666
      0.0055%
      European (Finnish)
      1 / 62,856
      0.0016%
      European (non-Finnish)
      7 / 1,162,110
      0.0006%
      + 3 not observed (Amish, Middle Eastern, Ashkenazi Jewish)
      gnomAD v2.1
      0.21% · 600 / 281,812
      3 hom · FAF 2.6%
      East Asian
      565 / 19,914
      2.8%
      3 hom
      Remaining individuals
      7 / 7,180
      0.097%
      African/African American
      19 / 24,850
      0.076%
      Admixed American
      6 / 35,376
      0.017%
      South Asian
      2 / 30,612
      0.0065%
      European (non-Finnish)
      1 / 128,946
      0.00078%
      + 2 not observed (Ashkenazi Jewish, European (Finnish))
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories).
      ClinVar ↗
      SpliceAI screenshot
      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 ↗
      Functional / OncoKB screenshot
      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. MLH3, a DNA mismatch repair protein, is infrequently altered in cancer.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      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).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      7Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots