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

VUS

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

BP4 (Supporting): intronic variant with SpliceAI max delta 0.01, predicting no splicing impact (at or below the 0.1 threshold).

2

No other criterion is met or applied, and a single BP4 (Supporting) satisfies no VCEP combination rule for Likely Benign (which requires one Benign.Strong plus one Benign.Supporting, or two Benign.Supporting); the variant is therefore classified as Variant of Uncertain Significance.

Final determination: Under the ClinGen InSiGHT MLH1 VCEP v2.0 criteria-combination framework, no rule fires when the only met criterion is BP4 supporting (Likely Benign requires 1 benign strong + 1 benign supporting or >=2 benign supporting; Benign requires >=2 benign strong or 1 stand-alone; no pathogenic criterion 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	Not met	Not met: this intronic duplication is not a null variant, and SpliceAI predicts no splicing impact (max delta 0.01).	cspec pvs1_variant_assessment spliceai gnomad_canada
PS1	Not met	Not met: the variant produces no amino acid change (p.?) and no pathogenic variant at the same nucleotide exists.	cspec spliceai
PS2	Not assessed	Not assessed: no proband phenotype or parental-testing data exists to establish a de novo event.	cspec clinvar PMID:25741868
PS3	Not assessed	Not assessed: no variant-specific functional, mRNA, or monoallelic expression assay data was available.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart clinvar
PS4	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares PS4 not applicable for this gene.	cspec
PM1	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares PM1 not applicable, and the intronic variant has no amino acid residue.	cspec
PM2	Not assessed	Not assessed: insufficient population-frequency evidence was available to apply PM2.
PM3	Not met	Not met: no biallelic CMMRD co-occurrence evidence exists, and gnomAD AF 0.053% far exceeds the <0.002% precondition.	cspec clinvar gnomad_v4 gnomad_v2 vcep_table_for_cmmrd_diagnosis
PM4	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares PM4 not applicable, and the intronic variant has no predicted protein change.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: the variant is an intronic duplication, not a missense change, so no amino acid residue comparison is possible.	cspec pm5_candidates
PM6	N/A	Not applicable: the InSiGHT MLH1 VCEP specification captures de novo evidence through the PS2 points system instead.	cspec PMID:25741868
PP1	Not assessed	Not assessed: no pedigree or segregation data exists to compute a co-segregation likelihood ratio.	cspec clinvar PMID:25741868
PP2	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares PP2 not applicable, and the variant is intronic rather than missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.01 is far below the 0.2 PP3 splice-threshold.	spliceai cspec
PP4	Not assessed	Not assessed: no variant-specific tumor data (MSI, MMR immunohistochemistry, or methylation) was available.	cspec
PP5	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares PP5 not applicable, and no expert-panel ClinVar classification exists.	cspec clinvar
BA1	Not assessed	Not assessed: insufficient population-frequency evidence was available to apply BA1.
BS1	Not assessed	Not assessed: insufficient population-frequency evidence was available to apply BS1.
BS2	Not assessed	Not assessed: insufficient population-frequency evidence was available to apply BS2.
BS3	Not assessed	Not assessed: no variant-specific mRNA or functional laboratory assay data was available to demonstrate proficient function.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart spliceai clinvar
BS4	Not assessed	Not assessed: no family segregation data exists; absence of data cannot demonstrate lack of co-segregation.	cspec clinvar PMID:25741868
BP1	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares BP1 not applicable, as missense variation is an established disease mechanism in MLH1.	cspec
BP2	N/A	Not applicable: the InSiGHT MLH1 VCEP specification replaces BP2 with BS2 for this gene.	cspec clinvar
BP3	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares BP3 not applicable, and the intronic insertion causes no coding change.	cspec gnomad_canada
BP4	Met	Met (Supporting): SpliceAI predicts no splicing impact (max delta 0.01, below the 0.1 threshold).	spliceai cspec
BP5	Not assessed	Not assessed: no variant-specific tumor data (MSS status, MMR immunohistochemistry, BRAF, methylation) was available.	cspec
BP6	N/A	Not applicable: the InSiGHT MLH1 VCEP specification declares BP6 not applicable, and no expert-panel ClinVar classification exists.	cspec clinvar
BP7	Not met	Not met: the variant lies at position -6, inside the splice-relevant window, not at or beyond -21 as BP7 requires.	cspec gnomad_canada spliceai

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.