Variant classification summary

NM_001040108.2:c.3455G>A

MLH3 · NP_001035197.1:p.(Arg1152His) · NM_001040108.2

GRCh37: chr14:75508328 C>T · GRCh38: chr14:75041625 C>T

Gene: MLH3 Transcript: NM_001040108.2

Final call

VUS

PM2 supporting

Variant details

Gene

MLH3

Transcript

NM_001040108.2

Protein

NP_001035197.1:p.(Arg1152His)

gnomAD AF

0.00012779092907727504 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely low population frequency — gnomAD v4.1 total AF 0.0128% (206/1,612,008 alleles), 0 homozygotes, absent from gnomAD-Canada — below the 0.1% calibration.

2

Synthesis: with a single supporting criterion and no other pathogenic or benign evidence, the variant is classified as Variant of Uncertain Significance under generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback combination rules were applied because no MLH3 VCEP/CSPEC final-classification framework is available; with only PM2 applied at supporting strength (1 supporting criterion), no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold is met, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: this is a missense substitution, so no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no pathogenic variant producing the same amino-acid change p.Arg1152His is established; the only ClinVar record for it is Uncertain significance.	clinvar PMID:25741868
PS2	Not assessed	Not assessed: no proband phenotype or parental testing results were available to evaluate a de novo origin.	clinvar PMID:25741868
PS3	Not assessed	Not assessed: no functional studies of this variant exist; OncoKB lists no variant-specific functional evidence for R1152H.	PMID:25741868 oncokb spliceai
PS4	Not assessed	Not assessed: no case-control study, case series, or affected-proband allele counts for this variant were available.	PMID:25741868 clinvar gnomad_v2
PM1	Not met	Not met: the variant is not in a statistically significant mutational hotspot, and no domain annotation places residue 1152 in a critical functional domain.	oncokb PMID:25741868
PM2	Met	Met (supporting): gnomAD v4.1 total allele frequency 0.0128% (206/1,612,008 alleles), 0 homozygotes, below the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context PMID:25741868 PMID:34043773
PM3	Not assessed	Not assessed: no observation of the variant in trans with a pathogenic MLH3 variant exists; phase data are lacking.	PMID:25741868 pvs1_gene_context clinvar gnomad_v4
PM4	N/A	Not applicable: missense substitution causes no protein-length change, so this in-frame/stop-loss criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at Arg1152 with a pathogenic classification was identified to serve as the required comparator.	pm5_candidates clinvar PMID:25741868
PM6	Not assessed	Not assessed: no parental testing or de novo assertion data were available.	clinvar PMID:25741868
PP1	Not assessed	Not assessed: no pedigree or segregation data were available to evaluate cosegregation with disease.	clinvar PMID:25741868
PP2	Not assessed	Not assessed: no missense-constraint data for MLH3 were available, and evidence favors loss-of-function rather than missense as the disease mechanism.	pvs1_gene_context PMID:25741868
PP3	Not met	Not met: SpliceAI max delta 0.06 and REVEL 0.361 both fall below their calibrated pathogenic thresholds.	spliceai revel bayesdel PMID:25741868
PP4	Not assessed	Not assessed: no confirmed proband phenotype or family history was available.	PMID:25741868 clinvar
PP5	Not met	Not met: no ClinVar expert-panel (VCEP) pathogenic classification exists for this exact variant; all six submissions are Uncertain significance.	clinvar PMID:25741868
BA1	Not met	Not met: highest observed allele frequency is 0.0163% (gnomAD v4.1 NFE), about 60-fold below the 1% stand-alone benign threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: highest observed allele frequency 0.0163% is below, not above, the expected disease allele frequency of ~0.17%.	gnomad_v2 gnomad_v4 PMID:25741868 PMID:34043773
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1/v4.1, and Lynch-type cancer risk is not fully penetrant at an early age, so the healthy-adult requirement is not satisfied.	gnomad_v2 gnomad_v4 PMID:25741868 PMID:34043773
BS3	Not assessed	Not assessed: no functional studies demonstrate normal function; in-silico predictions alone do not qualify as such evidence.	PMID:25741868 oncokb spliceai
BS4	Not assessed	Not assessed: no family or segregation data exist to demonstrate lack of segregation.	clinvar PMID:25741868
BP1	Not assessed	Not assessed: available evidence does not confirm that MLH3 disease is primarily caused by truncating variants.	pvs1_gene_context PMID:25741868
BP2	Not assessed	Not assessed: no cis/trans observation with a pathogenic variant exists, and a fully dominant MLH3 mechanism is not established.	PMID:25741868 clinvar
BP3	N/A	Not applicable: missense substitution causes no in-frame indel in a repetitive region, so this criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only one computational line supports no impact (SpliceAI max delta 0.06); REVEL 0.361 exceeds the 0.016 BP4 threshold.	spliceai revel bayesdel PMID:25741868
BP5	Not assessed	Not assessed: no proband-level molecular data were available to evaluate an alternate molecular basis for disease.	PMID:25741868 clinvar
BP6	Not met	Not met: no ClinVar expert-panel benign classification exists for this exact variant; all submissions are Uncertain significance.	clinvar PMID:25741868
BP7	N/A	Not applicable: missense substitution alters the protein sequence, so this synonymous-variant criterion does not apply.	generic_acmg_combination_rules

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