Variant classification summary

NM_001040108.2:c.628C>T

MLH3 · NP_001035197.1:p.(Arg210Ter) · NM_001040108.2

GRCh37: chr14:75515731 G>A · GRCh38: chr14:75049028 G>A

Gene: MLH3 Transcript: NM_001040108.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

MLH3

Transcript

NM_001040108.2

Protein

NP_001035197.1:p.(Arg210Ter)

gnomAD AF

4.7093290569320705e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (very strong): nonsense p.(Arg210Ter) in exon 2 of 13 with NMD predicted removes 85.6% of MLH3, including the C-terminal MLH1-interaction domain.

2

PM2 (supporting): gnomAD grpmax FAF 4.95e-05 (v4.1) and 2.30e-05 (v2.1) with zero homozygotes and absence from gnomAD-Canada, below the 0.0001 cut-off.

Final determination: Under generic ACMG/AMP 2015 combining rules as refined by the ClinGen SVI 2020 PM2 downgrade addendum, one very strong criterion (PVS1) plus one supporting criterion (PM2 supporting) yields Likely Pathogenic, short of the Pathogenic thresholds that require additional strong, moderate or supporting weight.

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	Met	Met at full strength: nonsense p.(Arg210Ter) in exon 2 of 13 removes 85.6% of MLH3 (1453 to 210 aa) with NMD predicted, so PVS1 is very strong.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context clinvar oncokb PMID:10615123 PMID:25741868 PMID:34043773 PMID:33516529 PMID:24493721
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001040108.2:c.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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
PS2	Not assessed	Not assessed: no proband or parental genotype data are available, so a confirmed de novo occurrence for c.628C>T cannot be established.	clinvar PMID:25741868 final_classification_framework pvs1_gene_context
PS3	Not met	Not met: no functional assay has tested c.628C>T, and the only MLH3 assay (engineered N-terminal deletion construct) does not address this variant.	PMID:10615123 oncokb PMID:25741868
PS4	Not met	Not met: no case-control or cohort enrichment data exists for c.628C>T, so prevalence in affected individuals cannot be shown to exceed gnomAD control frequency.	clinvar gnomad_v2 gnomad_v4 gnomad_canada PMID:24493721 PMID:33516529 PMID:34043773 PMID:25741868 PMID:10615123
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001040108.2:c.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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
PM2	Met	Met at Supporting: gnomAD v4.1 grpmax FAF 4.95e-05 sits below the <=0.0001 PM2 Supporting cut-off, with zero homozygotes and absence from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada final_classification_framework PMID:25741868
PM3	Not met	Not met: no MLH3 pathogenic variant is reported in trans with c.628C>T in any ClinVar submission or paper, so the recessive in-trans requirement is unmet.	clinvar pvs1_gene_context PMID:25741868
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.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). 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	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001040108.2:c.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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
PM6	Not assessed	Not assessed: with no proband and no parental phenotype or testing information, an assumed de novo occurrence cannot even be inferred.	clinvar PMID:25741868 PMID:10615123 final_classification_framework
PP1	Not assessed	Not assessed: no pedigree, affected relatives or genotype data exist, so no informative meioses can be counted for co-segregation.	clinvar PMID:25741868 PMID:24493721 PMID:33516529 PMID:34043773 pvs1_gene_context
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001040108.2:c.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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
PP3	N/A	Not applicable: c.628C>T is a nonsense variant, p.(Arg210Ter), outside the missense/splice-region scope of PP3.
PP4	Not assessed	Not assessed: no proband phenotype or family history is recorded, and MLH3 is absent from the Lynch-syndrome gene lists (MLH1, MSH2, MSH6, PMS2) cited in the guidelines.	PMID:34043773 PMID:33516529 PMID:24493721 PMID:10615123
PP5	Not met	Not met: ClinVar variation 860534 has zero expert-panel submissions; its three submissions are ordinary single-laboratory assertions (2 Uncertain significance, 1 Pathogenic).	clinvar PMID:24493721 PMID:33516529 PMID:34043773
BA1	Not met	Not met: highest population frequency is 6.10e-05 (gnomAD v4.1 European non-Finnish), roughly 820-fold below the >=0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada final_classification_framework PMID:25741868
BS1	Not met	Not met: peak ancestry frequency 6.10e-05 (gnomAD v4.1 European non-Finnish) is roughly 164-fold below the >=0.01 BS1 strong threshold.	gnomad_v2 gnomad_v4 gnomad_canada final_classification_framework
BS2	Not met	Not met: zero homozygotes in gnomAD v4.1 (1,613,818 alleles) and v2.1, and MLH3 disease is adult-onset rather than early-onset fully penetrant.	gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context PMID:34043773 PMID:33516529 PMID:25741868
BS3	Not met	Not met: no assay reports normal function for c.628C>T; the only MLH3 functional study tested an engineered deletion construct, not this variant.	PMID:10615123 oncokb PMID:25741868
BS4	Not assessed	Not assessed: no pedigree or relative genotypes exist, so non-segregation of c.628C>T with disease cannot be demonstrated.	clinvar PMID:25741868 PMID:24493721 PMID:33516529 PMID:34043773 final_classification_framework
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001040108.2:c.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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
BP2	Not met	Not met: no cis/trans phasing with a pathogenic variant is documented in any ClinVar submission or paper, and gnomAD reports zero homozygotes for c.628C>T.	clinvar gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
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.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). 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	N/A	Not applicable: c.628C>T is a truncating nonsense variant, outside the missense/splice-region scope of BP4.
BP5	Not met	Not met: no case carrying c.628C>T is reported with a documented alternate molecular basis of disease.	clinvar gnomad_v2 gnomad_v4 gnomad_canada PMID:34043773 PMID:33516529 PMID:24493721
BP6	Not met	Not met: ClinVar variation 860534 contains no expert-panel submission and no Benign or Likely benign assertion for c.628C>T.	clinvar
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.628C>T in MLH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001035197.1:p.(Arg210Ter). 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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