Variant classification summary

NM_000249.4:c.1039-6dupA

MLH1 · NP_000240.1:p.? · NM_000249.4

GRCh37: chr3:37067120 T>TA · GRCh38: chr3:37025629 T>TA

Gene: MLH1 Transcript: NM_000249.4

Final call

Benign

BA1 stand-alone benign BP4 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.?

gnomAD AF

0.0005303570529366187 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (stand-alone benign): gnomAD v4.1 grpmax FAF 0.00117 exceeds the 0.001 threshold, and the variant is excluded as a founder pathogenic variant.

2

BP4 (Supporting): intronic variant with SpliceAI max delta 0.01 (<=0.1), predicting no splicing impact.

3

Final classification: Benign, per InSiGHT MLH1 VCEP v2.0 Rule17 (Benign Stand-Alone via BA1).

Final determination: Rule17 of the ClinGen InSiGHT MLH1 VCEP v2.0 criteria-combination framework: exactly 1 criterion in the Benign.Stand Alone partition (BA1, met) is sufficient to classify the variant as Benign; no met pathogenic criterion exists to create conflicting evidence.

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 variant with no predicted protein consequence and SpliceAI max delta 0.01, so no loss-of-function mechanism is established.	cspec spliceai gnomad_canada gnomad_v4 gnomad_v2
PS1	Not met	Not met: no pathogenic splice variant at the same nucleotide exists for comparison, and SpliceAI max delta 0.01 predicts no splicing impact.	cspec spliceai clinvar
PS2	Not assessed	Not assessed: no de novo observation or parental testing data was reported for this variant.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay data was available - no calibrated assay odds, MMR function, or RNA expression results.	cspec vcep_functional_assay_svi_documentation_mmr clinvar PMID:25741868
PS4	N/A	Not applicable: the InSiGHT MLH1 VCEP captures case-control enrichment through PP4/BP5 instead of PS4.	cspec
PM1	N/A	Not applicable: this VCEP recognizes no mutational hot spots in MLH1, and the intronic variant alters no amino acid.	cspec
PM2	Not met	Not met: gnomAD v4.1 allele frequency 0.053% is more than 26-fold above the <0.002% PM2 rarity threshold.	gnomad_v4 cspec
PM3	Not met	Not met: no observation in trans with a pathogenic variant exists, and the 0.05% population frequency is far too high for a pathogenic Lynch syndrome allele.	cspec clinvar gnomad_v4 gnomad_v2
PM4	N/A	Not applicable: in-frame protein length change is not used by this VCEP, and the intronic duplication causes no protein-length change.	cspec
PM5	N/A	Not applicable: the intronic variant alters no amino acid residue, so no missense comparator exists.	cspec pm5_candidates
PM6	N/A	Not applicable: unconfirmed de novo events are scored through the PS2 points system in this VCEP.	cspec
PP1	Not assessed	Not assessed: no pedigree or segregation data was available to compute a co-segregation likelihood ratio.	cspec
PP2	N/A	Not applicable: this VCEP does not use the low-rate-of-benign-missense criterion, and the variant is intronic.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.01 is well below the >=0.2 splice-defect threshold, and missense scoring does not apply to this intronic variant.	spliceai cspec vcep_hci_priors_mlh1
PP4	Not assessed	Not assessed: no tumor phenotype data was available - no MSI status, MMR immunohistochemistry, or MLH1 promoter methylation results.	cspec clinvar
PP5	N/A	Not applicable: no ClinVar expert-panel classification exists for this variant, so the expert-panel rule cannot trigger.	cspec clinvar
BA1	Met	Met: gnomAD v4.1 grpmax FAF 0.00117 exceeds the >=0.001 stand-alone threshold, and the variant is excluded as a founder pathogenic variant. Flagged for review: grpmax FAF 0.00117 sits close to the 0.001 threshold, and gnomAD raw data flagged a low-complexity dupA context.	gnomad_v4 gnomad_v2 gnomad_canada clinvar cspec
BS1	Not met	Not met: grpmax FAF 0.00117 falls above the 0.01-0.1% BS1 band, so the variant instead meets the BA1 stand-alone threshold.	gnomad_v4 cspec
BS2	Not assessed	Not assessed: no patient-level genotype data was available, including any in-trans co-occurrence with a pathogenic variant.	cspec
BS3	Not assessed	Not assessed: no RNA-based or calibrated functional assay data existed to demonstrate normal splicing or protein function.	cspec vcep_functional_assay_svi_documentation_mmr spliceai clinvar PMID:25741868
BS4	Not assessed	Not assessed: no pedigrees were available to compute the required non-segregation likelihood ratio.	cspec
BP1	N/A	Not applicable: missense variants are an established MLH1 disease mechanism, and this intronic variant is not missense.	cspec
BP2	N/A	Not applicable: this VCEP handles co-occurrence through its own BS2 rule, superseding generic BP2.	cspec clinvar
BP3	N/A	Not applicable: in-frame repeat-region insertions are not used by this VCEP, and this is an intronic duplication.	cspec
BP4	Met	Met: intronic variant with SpliceAI max delta 0.01, at or below the <=0.1 no-splicing-impact threshold, meeting BP4 supporting.	spliceai cspec vcep_hci_priors_mlh1
BP5	Not assessed	Not assessed: no tumor phenotype data was available - no MSS status, MMR immunohistochemistry, BRAF V600E, or MLH1 methylation results.	cspec clinvar
BP6	N/A	Not applicable: no ClinVar expert-panel classification exists, and aggregate laboratory labels cannot trigger BP6.	cspec clinvar
BP7	Not met	Not met: the variant sits at intronic position -6, inside the splice-region window, not at or beyond -21/+7 as BP7 requires.	cspec spliceai

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