Variant classification summary

NM_000244.3:c.35C>G

MEN1 · NP_000235.2:p.(Pro12Arg) · NM_000244.3

GRCh37: chr11:64577547 G>C · GRCh38: chr11:64810075 G>C

Gene: MEN1 Transcript: NM_000244.3

Final call

VUS

PM2 supporting PM5 moderate PP3 moderate

Variant details

Gene

MEN1

Transcript

NM_000244.3

Protein

NP_000235.2:p.(Pro12Arg)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

2

PM5 moderate: same-residue p.Pro12Leu impaired menin-RPA2 binding.

3

PP3 moderate: REVEL 0.879 meets the moderate computational-evidence threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two moderate criteria plus one supporting criterion do not satisfy a listed Likely Pathogenic or Pathogenic combination, so the result is 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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000244.3:c.35C>G in MEN1 is a missense substitution predicted to produce NP_000235.2:p.(Pro12Arg). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing p.Pro12Arg was documented in the available evidence.
PS2	Not assessed	Not assessed: no parental genotypes or confirmed de novo observation are documented for the proband's NM_000244.3:c.35C>G variant.
PS3	Not assessed	Not assessed: no reviewed functional study directly tested MEN1 p.Pro12Arg, while same-codon p.Pro12Leu results cannot establish PS3 for p.Pro12Arg.	PMID:12509449 PMID:15254225 PMID:21264250 PMID:21819486 PMID:22090276
PS4	Not assessed	Not assessed: no exact-variant case-control counts or statistically significant phenotype-enrichment metric is available.	clinvar
PM1	Not assessed	Not assessed: no authoritative MEN1 critical-domain boundary or significant hotspot was available for residue 12.	PMID:12509449
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, with observed frequency 0 versus the generic PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: MEN1 is described as autosomal dominant, so the recessive biallelic/in-trans affected-proband PM3 framework does not apply.	PMID:23788249
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000244.3:c.35C>G in MEN1 is a missense substitution predicted to produce NP_000235.2:p.(Pro12Arg). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Met	Met at moderate strength: disease-associated P12L at the same residue impaired menin-RPA2 binding in a yeast two-hybrid assay.	PMID:12509449
PM6	Not assessed	Not assessed: no documented phenotype and negative family history support an assumed de novo MEN1 variant in the absence of parental testing.
PP1	Not assessed	Not assessed: no affected relatives, variant-positive family members, or informative meioses are documented for segregation analysis.
PP2	Not met	Not met: missense variants comprise approximately 10% of reported MEN1 mutations, so missense is not the predominant disease mechanism.	PMID:11739416
PP3	Met	Met at moderate strength: REVEL 0.879 exceeds the >=0.773 moderate PP3 threshold but is below the >=0.932 strong threshold.	revel
PP4	Not assessed	Not assessed: no patient-specific, highly specific MEN1 phenotype or family history is documented.	clinvar PMID:11739416
PP5	Not met	Not met: zero ClinVar expert-panel submissions exist for this exact variant, despite four Likely pathogenic laboratory records.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BS1 allele-frequency threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no healthy-individual or homozygote observation is reported; population databases instead report the variant as absent.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no reviewed assay directly demonstrated normal function for MEN1 p.Pro12Arg, and other MEN1 substitutions cannot establish BS3 for this variant.	PMID:12509449 PMID:15254225 PMID:21264250 PMID:21819486 PMID:22090276
BS4	Not assessed	Not assessed: no unaffected variant-positive relatives or phenotype-based non-segregation observations are documented.
BP1	Not met	Not met: MEN1 includes disease-associated missense variants, including same-residue P12L with impaired menin-RPA2 binding.	PMID:11739416 PMID:12509449
BP2	Not assessed	Not assessed: no affected-proband genotype, cis/trans phase, or co-occurring pathogenic/benign allele is documented.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000244.3:c.35C>G in MEN1 is a missense substitution predicted to produce NP_000235.2:p.(Pro12Arg). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.879 exceeds the most permissive <=0.29 supporting BP4 threshold for benign computational evidence.	revel
BP5	Not assessed	Not assessed: no patient-level evidence shows an alternative molecular diagnosis explaining the relevant phenotype.	clinvar
BP6	Not met	Not met: zero ClinVar expert-panel submissions provide an exact-variant Benign or Likely benign classification.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000244.3:c.35C>G in MEN1 is a missense substitution predicted to produce NP_000235.2:p.(Pro12Arg). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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