Variant classification summary

NM_000249.4:c.232G>C

MLH1 · NP_000240.1:p.(Glu78Gln) · NM_000249.4

GRCh37: chr3:37042470 G>C · GRCh38: chr3:37000979 G>C

Gene: MLH1 Transcript: NM_000249.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.(Glu78Gln)

gnomAD AF

1.2440983086483494e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: gnomAD v4 allele frequency is 1.2441e-06, below 0.00002.

2

PP3 Supporting: the MLH1 HCI prior for c.232G>C (p.E78Q) is 0.7144, within the VCEP Supporting interval.

3

VUS: PM2 and PP3 do not satisfy any VCEP pathogenic or benign combination rule.

Final determination: Under the MLH1 VCEP Version 2.0 framework, PM2 Supporting plus PP3 Supporting does not satisfy a 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: c.232G>C is missense p.Glu78Gln, while the VCEP PVS1 rule is explicitly marked Not Applicable for this criterion.	cspec
PS1	Not assessed	Not assessed: no VCEP-established Pathogenic variant with a different nucleotide change encoding p.Glu78Gln was identified.	cspec pm5_candidates clinvar
PS2	Not assessed	Not assessed: no documented de novo observation, parental testing, or de novo point total is available for this variant.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional readout, functional odds, or qualifying RNA result is available to compare with the VCEP PS3 thresholds.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:25394175
PS4	N/A	Not applicable: the MLH1 VCEP excludes proband-counting PS4 because tumor IHC evidence is evaluated through PP4.	cspec PMID:25394175 vcep_vcep_pilot_variants_mmr
PM1	N/A	Not applicable: the MLH1 VCEP explicitly marks PM1 Not Applicable despite residue 78 lying within listed functional domains.	cspec vcep_mmr_functional_domains
PM2	Met	Met at supporting: gnomAD v4 total AF is 1.2441e-06, below the VCEP PM2 threshold of 0.00002 (1 in 50,000 alleles).	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
PM3	Not assessed	Not assessed: gnomAD grpmax FAF is 3.65e-06, but no affected-proband second MLH1 variant or phase information is available to assign PM3 points.	cspec gnomad_v4
PM4	N/A	Not applicable: the VCEP explicitly marks PM4 Not Applicable, and c.232G>C is a missense substitution without a VCEP PM4 path.	cspec
PM5	Not assessed	Not assessed: zero same-residue missense comparator candidates were identified for the required VCEP Pathogenic or Likely Pathogenic comparison.	cspec pm5_candidates vcep_hci_priors_mlh1
PM6	N/A	Not applicable: the MLH1 VCEP explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no pedigree data, informative meioses, or combined Bayes Likelihood Ratio is available for co-segregation evaluation.	cspec
PP2	N/A	Not applicable: the MLH1 VCEP explicitly marks PP2 Not Applicable.	cspec
PP3	Met	Met at Supporting: HCI prior probability is 0.7144, within the VCEP PP3 Supporting range (>0.68 and ≤0.81).	cspec vcep_hci_priors_mlh1
PP4	Not assessed	Not assessed: no patient tumor MSI/IHC findings or MLH1-methylation exclusion are available to evaluate the PP4 Supporting requirement.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the MLH1 VCEP prohibits PP5, regardless of the single-submitter ClinVar classification or referral-guideline citation.	cspec clinvar PMID:25394175 vcep_vcep_pilot_variants_mmr
BA1	Not met	Not met: gnomAD v4 grpmax FAF is 3.65e-06, below the VCEP BA1 threshold of 0.001 (0.1%).	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
BS1	Not met	Not met: gnomAD v4 grpmax FAF is 3.65e-06, below the VCEP BS1 lower threshold of 0.0001 (0.01%).	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
BS2	Not assessed	Not assessed: no individual-level in-trans co-occurrence, confirmed phase, age, and CMMRD information is available for the BS2 rule.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
BS3	Not assessed	Not assessed: no variant-specific proficient-function result or calibrated functional odds is available to compare with the VCEP BS3 thresholds.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:25394175
BS4	Not assessed	Not assessed: no non-segregating relatives, informative pedigree data, or combined Bayes Likelihood Ratio is available.	cspec
BP1	N/A	Not applicable: the MLH1 VCEP explicitly marks BP1 Not Applicable.	cspec
BP2	N/A	Not applicable: the MLH1 VCEP marks BP2 not applicable and directs that BS2 is used instead.	cspec
BP3	N/A	Not applicable: the VCEP explicitly marks BP3 Not Applicable, and c.232G>C is missense rather than an applicable repeat-region in-frame indel.	cspec
BP4	Not met	Not met: HCI prior probability is 0.7144, not below the VCEP BP4 cutoff of 0.11 for missense variants.	cspec vcep_hci_priors_mlh1
BP5	Not assessed	Not assessed: no tumor MSS, MMR-protein, BRAF V600E, or MLH1-methylation findings are available to establish an alternate molecular basis.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
BP6	N/A	Not applicable: the MLH1 VCEP prohibits BP6, and the available ClinVar submission is uncertain significance rather than a qualifying benign report.	cspec clinvar vcep_vcep_pilot_variants_mmr
BP7	N/A	Not applicable: c.232G>C causes the missense substitution p.Glu78Gln, whereas BP7 covers only synonymous or intronic variants.	cspec

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