Classification rationale

PM2 BP4 VUS

MLH3 c.1910G>A

The MLH3 c.1910G>A (p.Arg637His, p.R637H) variant has been reported in ClinVar, where current submissions classify it as a variant of uncertain significance.¹ This variant is rare in population databases, with a total allele frequency of 0.00425% in gnomAD v2.1 and 0.00149% in gnomAD v4.1, and it is absent from gnomAD-Canada v1.0.² Available computational evidence does not support a damaging effect: REVEL is 0.103, BayesDel is -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 revelbayesdelspliceai ↗

Gene diagram · NM_001040108.2 · variants mapped to exon structure

MLH3 NM_001040108.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate review Pathogenic

Population frequency is below the 0.1% rarity threshold used for generic ACMG review. The variant is present at 0.00425% in gnomAD v2.1 and 0.00149% in gnomAD v4.1, with no homozygotes in either dataset, and it is absent from gnomAD-Canada v1.0.

gnomAD v2.1 total AF 4.24809e-05 (12/282480)0 homozygotes.gnomAD v4.1 total AF 1.4869e-05 (24/1614096)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting review Benign

Multiple computational findings support no deleterious effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

REVEL 0.103 supports a benign missense prediction.BayesDel -0.485573 supports a benign prediction.SpliceAI max delta 0.00 argues against splice disruption.

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No evidence was identified that a different nucleotide change causing the same Arg637His protein effect has already been established as pathogenic or likely pathogenic.

PS2 No confirmed de novo occurrence data were identified for this variant.

PS3 No published well-established functional study demonstrating a damaging effect of this specific variant was identified.

PS4 No case-control enrichment data or multiple independent affected observations sufficient to show increased prevalence in affected individuals were identified for this variant.

PM1 This variant has not been identified in a well-established functional domain or statistically significant hotspot, and Cancer Hotspots did not show a significant hotspot signal at residue R637.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context.

PM6 No assumed de novo occurrence data were identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish that MLH3 missense variation in general is a common mechanism of disease with sufficiently low benign missense background to support PP2.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype, family history, or tumor-feature evidence specific enough to support a highly characteristic disease presentation was identified for this variant.

Benign

BA1 Population frequency does not meet the benign stand-alone threshold of greater than 1%.

BS1 Population frequency does not exceed the benign strong threshold of greater than 0.3%.

BS2 No evidence was identified showing this variant in healthy adults in a context sufficient to establish BS2.

BS3 No well-established functional study demonstrating normal or near-normal function for this specific variant was identified.

BS4 No non-segregation data were identified for this variant.

BP1 Available evidence does not establish that missense variation in MLH3 is a clearly low-risk mechanism relative to truncating variants, so BP1 was not applied.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant.

BP5 No alternate molecular cause explaining the reported phenotype was identified, so BP5 could not be assessed.

N/A · 7 PVS1 · PM4 · PM5 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.4869e-05; MAF= 0.00149%, 24/1614096 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0); grpmax FAF= 6.763e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.24809e-05; MAF= 0.00425%, 12/282480 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228758; MAF= 0.02288%, 7/30600 alleles, homozygotes = 0); grpmax FAF= 0.00010661.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0015% · 24 / 1,614,096
0 hom · FAF 0.0068%

Middle Eastern 1 / 6,062	0.016%
South Asian 11 / 91,076	0.012%
African/African American 8 / 75,024	0.011%
Remaining individuals 2 / 62,506	0.0032%
East Asian 1 / 44,882	0.0022%
Admixed American 1 / 60,018	0.0017%

+ 4 not observed (European (Finnish), Amish, Ashkenazi Jewish, European (non-Finnish))

gnomAD v2.1

0.0042% · 12 / 282,480
0 hom · FAF 0.011%

South Asian 7 / 30,600	0.023%
African/African American 3 / 24,964	0.012%
East Asian 2 / 19,948	0.01%

+ 5 not observed (Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1782502)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.103. BayesDel score = -0.485573.

SpliceAI ↗

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

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; COSV53152155, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

34043773 ↗ European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?