Variant classification summary

NM_000249.4:c.1759A>G

MLH1 · NP_000240.1:p.(Met587Val) · NM_000249.4

GRCh37: chr3:37089037 A>G · GRCh38: chr3:37047546 A>G

Gene: MLH1 Transcript: NM_000249.4

Final call

VUS

PM2 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.(Met587Val)

gnomAD AF

3.979782703864369e-06 (v2.1)

ClinVar

Uncertain significance

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: the variant is absent from gnomAD v4.1, meeting the VCEP rarity threshold.

Final determination: Under the MLH1 VCEP Version 2.0 framework, PM2 Supporting alone satisfies no pathogenic or benign combination rule, so the variant is classified as VUS.

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	Not applicable: the variant is missense p.(Met587Val), whereas the VCEP PVS1 rule names null, qualifying splice, structural, RNA-splicing, and initiation-codon variants.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not met	Not met: no different nucleotide change encoding p.Met587Val was established as Pathogenic by the MLH1 VCEP in the searched governing materials.	cspec vcep_hci_priors_mlh1
PS2	Not assessed	Not assessed: no documented de novo result, parental confirmation, qualifying LS-spectrum tumor, or VCEP de novo-point assignment is available.	cspec
PS3	Not assessed	Not assessed: no variant-specific calibrated functional odds or flowchart-qualified MMR function-defect result is available.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:18206535
PS4	N/A	Not applicable: the MLH1 VCEP explicitly excludes PS4 proband counting because tumor IHC data are available for classification through PP4.	cspec
PM1	N/A	Not applicable: the governing MLH1 CSPEC explicitly designates PM1 as Not Applicable, and no authoritative MLH1 domain-table entry is present.	cspec vcep_mmr_functional_domains
PM2	Met	Met, Supporting: the variant is absent from gnomAD v4.1, satisfying the VCEP PM2 threshold of <0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: PM2_Supporting is met because the variant is absent from gnomAD v4.1, but no second MLH1 variant or phase/CMMRD evidence is available.	cspec gnomad_v4
PM4	N/A	Not applicable: the variant is a missense substitution with no protein-length change, and the MLH1 VCEP marks PM4 not applicable.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PM5	Not met	Not met: the target HCI prior is 0.5956, below the VCEP PP3-supporting threshold of >0.68 required before PM5 can be used.	cspec vcep_hci_priors_mlh1
PM6	N/A	Not applicable: the MLH1 VCEP specification explicitly marks PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: no informative pedigree observations or combined Bayes likelihood ratio is available to compare with the VCEP PP1 thresholds.	cspec
PP2	N/A	Not applicable: the governing MLH1 CSPEC explicitly designates PP2 as Not Applicable.	cspec
PP3	Not met	Not met: HCI prior probability 0.5956 is below the VCEP PP3 Supporting threshold of >0.68 for missense variants.	cspec vcep_hci_priors_mlh1
PP4	Not assessed	Not assessed: no qualifying CRC/endometrial MSI-H or consistent MMR-protein-loss evidence with excluded MLH1 methylation is documented.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the MLH1 VCEP explicitly states that PP5 is not for use under the VCEP recommendation.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v4.1, below the VCEP's BA1 threshold of >=0.001 (0.1%).	cspec gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v4.1, below the VCEP's BS1 frequency interval of 0.0001 to <0.001.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no documented qualifying trans co-occurrence, clinical eligibility, CMMRD assessment, or parental/offspring phase confirmation is available.	cspec
BS3	Not assessed	Not assessed: no variant-specific calibrated functional odds or flowchart-qualified proficient protein or mRNA assay result is available.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:18206535
BS4	Not assessed	Not assessed: no non-segregation observation or combined Bayes likelihood ratio is available to compare with the VCEP BS4 thresholds.	cspec
BP1	N/A	Not applicable: the governing MLH1 CSPEC explicitly designates BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the MLH1 VCEP excludes BP2 and directs users to apply BS2 instead.	cspec
BP3	N/A	Not applicable: BP3 is limited to in-frame indels in nonfunctional repetitive regions, whereas this variant is missense p.(Met587Val).	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
BP4	Not met	Not met: HCI prior probability 0.5956 is not below the VCEP BP4 threshold of <0.11 for missense variants.	cspec vcep_hci_priors_mlh1
BP5	Not assessed	Not assessed: no qualifying MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor evidence is documented for this patient.	cspec
BP6	N/A	Not applicable: the MLH1 VCEP explicitly states that BP6 is not for use under the VCEP recommendation.	cspec
BP7	N/A	Not applicable: c.1759A>G causes the missense substitution p.Met587Val, not a synonymous or qualifying intronic variant.	cspec

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