NM_001040108.2:c.2390G>A

MLH3 · NP_001035197.1:p.(Arg797His) · NM_001040108.2

GRCh37: chr14:75513969 C>T · GRCh38: chr14:75047266 C>T

Gene: MLH3 Transcript: NM_001040108.2

Final call

Benign

BA1 stand-alone benign BS1 strong BP1 supporting BP4 moderate

Variant details

Gene

MLH3

Transcript

NM_001040108.2

Protein

NP_001035197.1:p.(Arg797His)

gnomAD AF

0.003508521935232053 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BA1 stand-alone benign: the allele reaches a popmax filtering frequency of 0.0633 (gnomAD v2.1) and 0.0647 (gnomAD v4.1) in African ancestry, above 5%.

BS1 strong: that same 0.063-0.065 popmax filtering frequency is well above the 0.01 strong benign threshold.

BP1 supporting: MLH3 disease alleles are predominantly truncating, with 2,175 of 2,176 ClinVar missense variants uncertain, conflicting or benign.

BP4 moderate: REVEL 0.083 places this missense substitution at or below the moderate benign in-silico threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback rules, a single stand-alone benign criterion (BA1) is sufficient for a Benign classification, and the combination of BA1 plus BS1 strong, BP1 supporting and BP4 moderate meets that rule.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001040108.2:c.2390G>A in MLH3 is a missense substitution predicted to produce NP_001035197.1:p.(Arg797His). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic variant shares this p.Arg797His change - the only ClinVar record carrying it is Benign across 13 submissions.	clinvar PMID:25741868
PS2	Not assessed	Not assessed: no proband or parental genotypes exist in the record, so de novo status cannot be tested.	clinvar gnomad_v2 gnomad_v4 PMID:25741868
PS3	Not assessed	Not assessed: no functional assay of MLH3 p.Arg797His was found; OncoKB reports no variant-specific functional evidence for this variant.	PMID:25741868 oncokb clinvar
PS4	Not met	Not met: no case-control or case-enrichment evidence exists, and gnomAD v4.1 grpmax AF 0.0647 (174 homozygotes) precludes enrichment in affected cases.	clinvar gnomad_v4 gnomad_v2 PMID:25741868 PMID:24493721 PMID:33516529 PMID:34043773
PM1	Not met	Not met: residue 797 lies outside MLH3's annotated ATPase (~1-349) and C-terminal MutL (~1189-1403) domains, is not a significant hotspot, and carries benign variation up to 6.61% popmax.	final_classification_framework clinvar gnomad_v2 gnomad_v4
PM2	Not met	Not met: the allele is present at 0.35% overall in gnomAD v4.1 and 6.6% in African ancestry, far above the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada clinvar PMID:25741868 PMID:34043773
PM3	Not met	Not met: no pathogenic MLH3 variant in trans is reported, and this common allele (gnomAD v2.1 AF 0.64%, 72 homozygotes) is tolerated biallelically.	generic_acmg_combination_rules PMID:25741868 clinvar gnomad_v2 gnomad_v4 PMID:34043773
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001040108.2:c.2390G>A in MLH3 is a missense substitution predicted to produce NP_001035197.1:p.(Arg797His). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: the other missense variants at codon 797 are uncertain or likely benign (p.Arg797Cys: 2 VUS + 1 likely benign; p.Arg797Asp: VUS), with none pathogenic.	clinvar pm5_candidates PMID:25741868
PM6	Not assessed	Not assessed: no proband and no assumed-de-novo observation were recorded, despite 174 homozygotes in gnomAD.	clinvar gnomad_v2 gnomad_v4 PMID:25741868
PP1	Not assessed	Not assessed: no pedigree or relative genotypes exist, leaving zero informative meioses for a segregation test.	PMID:25741868 PMID:24493721
PP2	Not met	Not met: MLH3 is missense-tolerant (gnomAD v2.1 mis_z 0.74, oe_mis 0.92) and missense is not an established mechanism (1 of 2,176 ClinVar missense variants P/LP).	gnomad_v2 clinvar pvs1_gene_context PMID:34043773 PMID:25741868
PP3	Not met	Not met: REVEL 0.083 is far below the >=0.644 supporting PP3 threshold for this missense variant.	revel
PP4	Not assessed	Not assessed: the case supplies no proband phenotype or family history, and MLH3 is absent from the MMR gene sets that define a specific phenotype (PMID:34043773).	PMID:34043773 PMID:24493721 PMID:33516529
PP5	Not met	Not met: ClinVar VCV000314383 has 13 submissions from clinical laboratories and zero expert-panel classifications, none asserting pathogenic, so PP5's expert-panel prerequisite is absent.	clinvar PMID:25741868
BA1	Met	Met, stand-alone: the African-ancestry popmax filtering AF is 0.0633 in gnomAD v2.1 and 0.0647 in v4.1, both above the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada clinvar PMID:25741868 generic_acmg_combination_rules
BS1	Met	Met at strong: the popmax filtering AF of 0.063-0.065 exceeds the 0.01 BS1 threshold, on the same observation that already drives the stand-alone BA1 call.	gnomad_v2 gnomad_v4 gnomad_canada clinvar PMID:25741868 PMID:34043773 generic_acmg_combination_rules
BS2	N/A	Not applicable: MLH3-associated hereditary cancer is adult-onset with variable penetrance, so the fully-penetrant-at-an-early-age precondition for BS2 is not satisfied.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:34043773 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no MLH3 p.Arg797His functional assay exists, and the REVEL 0.083 in-silico score is not BS3 experimental evidence.	PMID:25741868 oncokb clinvar
BS4	Not assessed	Not assessed: no family genotypes exist, so non-segregation cannot be shown and 174 gnomAD homozygotes are not a BS4 finding.	gnomad_v2 gnomad_v4 PMID:25741868
BP1	Met	Met at supporting: MLH3 disease alleles are predominantly truncating (nonsense, frameshift, splice), with 2,175 of 2,176 ClinVar missense variants uncertain, conflicting or benign.	clinvar pvs1_gene_context gnomad_v2 PMID:34043773 PMID:25741868
BP2	Not met	Not met: no source places this variant in cis or in trans with a pathogenic allele; none of 13 ClinVar submissions reports phase.	generic_acmg_combination_rules PMID:25741868 clinvar PMID:34043773 PMID:33516529 PMID:24493721 gnomad_v2 gnomad_v4
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001040108.2:c.2390G>A in MLH3 is a missense substitution predicted to produce NP_001035197.1:p.(Arg797His). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at moderate strength: REVEL 0.083 sits at or below the <=0.183 moderate BP4 threshold for this missense variant.	revel
BP5	Not assessed	Not assessed: no proband-level genotype data exist and no ClinVar submission documents a co-occurring alternate molecular cause for c.2390G>A.	clinvar PMID:25741868 PMID:28492532
BP6	Not met	Not met: the Benign ClinVar label on VCV000314383 is a 2-star aggregate of 12 laboratory submissions with zero expert-panel submissions, so BP6's expert-panel prerequisite is absent.	clinvar PMID:25741868
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001040108.2:c.2390G>A in MLH3 is a missense substitution predicted to produce NP_001035197.1:p.(Arg797His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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