Variant classification summary

NM_001040108.2:c.3828-24dup

MLH3 · NP_001035197.1:p.? · NM_001040108.2

GRCh37: chr14:75497428 T>TA · GRCh38: chr14:75030725 T>TA

Gene: MLH3 Transcript: NM_001040108.2

Final call

Benign

BA1 stand-alone benign BS1 strong BP4 supporting

Variant details

Gene

MLH3

Transcript

NM_001040108.2

Protein

NP_001035197.1:p.?

gnomAD AF

0.012967504744209053 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (Stand-alone benign): gnomAD v4.1 total allele frequency 1.297% far exceeds the 1% threshold for a common benign polymorphism.

2

BS1 (Strong): allele frequency exceeds the 0.3% threshold expected for MLH3-associated disease.

3

BP4 (Supporting): SpliceAI max delta 0.056 is below the 0.1 threshold, predicting no splice impact.

4

Overall: Benign, per generic ACMG/AMP 2015 combination rules with BA1 alone at stand-alone strength.

Final determination: Under the generic ACMG/AMP 2015 fallback (no MLH3 VCEP/CSPEC), BA1 stand-alone benign is met, which alone classifies the variant as Benign; BS1 strong plus BP4 supporting provide additional benign evidence and there are no met pathogenic criteria to conflict.

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	Not met	Not met: intronic duplication is not a null variant, and SpliceAI predicts no truncating splice effect (max delta 0.056).	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework spliceai gnomad_canada PMID:25741868
PS1	N/A	Not applicable: intronic duplication produces no amino acid change (p.?) to compare with a known pathogenic variant.	PMID:25741868 gnomad_canada
PS2	Not assessed	Not assessed: no proband or parental-testing data available to establish a de novo origin.	clinvar PMID:25741868 generic_acmg_combination_rules
PS3	Not met	Not met: no functional study of this variant exists to demonstrate a deleterious effect.	PMID:25741868
PS4	Not met	Not met: no case-control enrichment; variant is a common polymorphism (gnomAD v4.1 AF 1.297%).	PMID:25741868 gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: intronic variant changes no amino acid, so no protein hotspot or domain position applies.	PMID:25741868 gnomad_canada
PM2	Not met	Not met: allele frequency (gnomAD v4.1 1.297%) far exceeds the <0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband or phase data available to evaluate trans inheritance.	PMID:25741868 clinvar gnomad_v4 gnomad_v2
PM4	N/A	Not applicable: intronic duplication causes no protein-length change (p.?).	pvs1_variant_assessment spliceai PMID:25741868
PM5	N/A	Not applicable: not a missense variant; no amino acid residue for same-residue comparison.	PMID:25741868 pm5_candidates
PM6	Not assessed	Not assessed: no proband or parental-testing data to document an assumed de novo origin.	clinvar PMID:25741868 generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no affected-family segregation data or meioses reported.	clinvar PMID:25741868 generic_acmg_combination_rules
PP2	N/A	Not applicable: criterion applies to missense variants; this is an intronic duplication with no amino acid change.	PMID:25741868 gnomad_canada
PP3	Not met	Not met: SpliceAI max delta 0.056 is below the >0.2 PP3 splice-impact threshold.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or family history available to evaluate specificity.	clinvar PMID:25741868
PP5	Not met	Not met: ClinVar submission is single-submitter Likely benign, not an expert-panel pathogenic classification.	clinvar PMID:25741868
BA1	Met	Met (stand-alone benign): gnomAD v4.1 total allele frequency 1.297% exceeds the >1% BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Met	Met (strong): gnomAD v4.1 total allele frequency 1.297% exceeds the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: homozygotes observed (8 in gnomAD v4.1), but MLH3 disease is adult-onset and incompletely penetrant.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not met	Not met: no functional assay demonstrates preserved function; the SpliceAI prediction alone is insufficient.	spliceai PMID:25741868
BS4	Not assessed	Not assessed: no family testing or non-segregation observations available.	clinvar PMID:25741868 generic_acmg_combination_rules
BP1	N/A	Not applicable: criterion applies to missense variants; this is an intronic duplication.	PMID:25741868 gnomad_canada
BP2	Not assessed	Not assessed: no cis/trans co-occurrence or phase data available.	PMID:25741868 clinvar gnomad_v4
BP3	N/A	Not applicable: no protein-level in-frame indel demonstrated for this intronic duplication.	gnomad_canada gnomad_v4 PMID:25741868
BP4	Met	Met (supporting): SpliceAI max delta 0.056 is below the <0.1 BP4 threshold, predicting no splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband data on an alternate molecular basis for disease.	PMID:25741868
BP6	Not met	Not met: ClinVar Likely benign is a single ordinary laboratory submission, not an expert-panel classification.	clinvar PMID:25741868
BP7	N/A	Not applicable: criterion applies to synonymous coding variants; this is an intronic duplication.	PMID:25741868

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.