Variant classification summary

NM_000249.4:c.350C>T

MLH1 · NP_000240.1:p.(Thr117Met) · NM_000249.4

GRCh37: chr3:37045935 C>T · GRCh38: chr3:37004444 C>T

Gene: MLH1 Transcript: NM_000249.4

Final call

Likely Pathogenic

PS3 moderate PM2 supporting PP3 moderate PP5 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.(Thr117Met)

gnomAD AF

7.434833682770517e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 Moderate reports mismatch-repair deficiency for T117M in a human functional assay.

2

Pathogenic evidence: PM2 Supporting reflects an extremely rare gnomAD v4.1 allele frequency of 7.43483e-06.

3

Pathogenic evidence: PP3 Moderate is supported by an exact MLH1 HCI pathogenicity prior of 0.893.

4

Pathogenic evidence: PP5 Supporting records an InSiGHT expert-panel Pathogenic classification.

Final determination: VCEP Rule14 is satisfied by two Pathogenic Moderate criteria (PS3 and PP3) and at least two Pathogenic Supporting criteria (PM2 and PP5), resulting in Likely Pathogenic.

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: c.350C>T is a missense substitution, while the VCEP PVS1 rule covers null, qualifying splice, structural, and initiation-codon variants.	cspec vcep_pvs1_decisiontree_mmr pvs1_variant_assessment vcep_vcep_pilot_variants_mmr
PS1	Not assessed	Not assessed: no alternate-nucleotide variant producing the same p.Thr117Met amino-acid change was identified as VCEP-Pathogenic in the available evidence.	cspec vcep_vcep_pilot_variants_mmr
PS2	Not assessed	Not assessed: no documented parental confirmation, de novo point total, or qualifying LS-spectrum tumor evidence is available for the VCEP's PS2 thresholds.	clinvar cspec
PS3	Met	Met at Moderate: T117M was MMR-deficient in a human expression/complementation assay, with wild-type repair near 86.5% versus deficient T117M function.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:11781295
PS4	N/A	Not applicable: the MLH1 Version 2.0 VCEP explicitly marks PS4 as Not Applicable.	cspec
PM1	N/A	Not applicable: residue 117 lies in MLH1 functional domains, but the VCEP explicitly excludes hotspot/domain evidence from PM1.	cspec vcep_mmr_functional_domains
PM2	Met	Met at supporting: gnomAD v4.1 AF is 7.43483e-06, below the VCEP PM2 threshold of <0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: gnomAD v4.1 grpmax FAF is 5.53e-06, but no qualifying second MLH1 variant, affected-proband CMMRD observation, or phase information is available.	cspec gnomad_v4
PM4	N/A	Not applicable: the MLH1 VCEP explicitly marks PM4 Not Applicable, and c.350C>T is a missense substitution without a protein-length change.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PM5	Not met	Not met: p.Thr117Arg is VCEP Likely pathogenic, but the HCI prior is 0.893, corresponding to PP3 Moderate rather than required PP3 Supporting.	cspec vcep_vcep_pilot_variants_mmr vcep_hci_priors_mlh1
PM6	N/A	Not applicable: the MLH1 VCEP marks PM6 not applicable and directs de novo assessment to PS2.	cspec
PP1	Not assessed	Not assessed: no pedigree observations, informative meioses, family count, or combined Bayes Likelihood Ratio is available for the VCEP PP1 thresholds.	clinvar cspec
PP2	N/A	Not applicable: the MLH1 VCEP explicitly excludes PP2 for missense variants under this specification.	cspec
PP3	Met	Met at Moderate: the exact HCI prior for MLH1 c.350C>T is 0.893, exceeding the VCEP PP3_Moderate threshold of >0.81.	cspec vcep_hci_priors_mlh1
PP4	Not assessed	Not assessed: no patient-level MSI, MMR-protein, or MLH1-methylation results are available to satisfy the PP4 tumor rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	Met	Not applicable: the MLH1 Version 2.0 VCEP explicitly marks PP5 as Not Applicable.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 5.53e-06, below the VCEP BA1 threshold of ≥0.001.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 5.53e-06, below the VCEP BS1 lower threshold of 0.0001.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence with phase confirmation and the VCEP-required clinical exclusions is documented.	cspec
BS3	Not met	Not met: T117M was reported MMR-deficient, whereas BS3 requires calibrated pathogenicity odds <=0.05 or variant-specific proficient function.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:11781295
BS4	Not assessed	Not assessed: no non-segregating relatives, informative meioses, pedigree data, or combined Bayes Likelihood Ratio is available for the VCEP BS4 thresholds.	clinvar cspec
BP1	N/A	Not applicable: the MLH1 VCEP excludes BP1 because missense variation is not limited to a loss-of-function-only disease mechanism.	cspec
BP2	N/A	Not applicable: the MLH1 VCEP marks BP2 as not applicable and directs use of BS2 instead.	cspec
BP3	N/A	Not applicable: the MLH1 VCEP explicitly marks BP3 Not Applicable, and c.350C>T is missense rather than an in-frame indel in a repeat region.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
BP4	Not met	Not met: the exact HCI prior is 0.893, not <0.11, and the VCEP's SpliceAI BP4 path is limited to intronic or synonymous variants.	cspec vcep_hci_priors_mlh1
BP5	Not assessed	Not assessed: no patient-level tumor, MSS/MSI, MMR-protein, BRAF V600E, or MLH1-methylation data are available for BP5.	cspec
BP6	N/A	Not applicable: the MLH1 Version 2.0 VCEP explicitly marks BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: c.350C>T is a missense variant, whereas VCEP BP7 covers only synonymous or intronic variants.	cspec

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