Classification rationale

PM2PM5PP3 VUS

MEN1 c.35C>G missense · exon 2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1. PM5 moderate: same-residue p.Pro12Leu impaired menin-RPA2 binding. PP3 moderate: REVEL 0.879 meets the moderate computational-evidence threshold.

PM2 + PM5 + PP3 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000244.3 · variants mapped to exon structure

MEN1 NM_000244.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

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 v2.1 reports the exact variant as absent; the queried record is the exome dataset.gnomAD v4.1 reports the exact variant as absent.The available gnomAD v2.1 non-cancer exome-only subset reports the variant as absent.

gnomad_v2 ↗gnomad_v4 ↗

PM5 moderate Pathogenic

Met at moderate strength: disease-associated P12L at the same residue impaired menin-RPA2 binding in a yeast two-hybrid assay.

The study tested 15 disease-associated MEN1 missense mutations and reported that P12L, the alternate substitution at residue 12, impaired menin-RPA2 binding to a variable degree.The P12L result is used as same-residue comparator evidence for PM5 and is not extrapolated as a direct functional assay result for P12R.

PMID:12509449 ↗

PP3 moderate Pathogenic

Met at moderate strength: REVEL 0.879 exceeds the >=0.773 moderate PP3 threshold but is below the >=0.932 strong threshold.

The normalized consequence is missense: NM_000244.3:c.35C>G, NP_000235.2:p.(Pro12Arg).The REVEL score is 0.879, meeting the moderate PP3 threshold of >=0.773 and not meeting the strong threshold of >=0.932.The thresholds are the supplied ClinGen SVI REVEL calibration values from Pejaver et al. (2022), PMID:36413997.

Assessed · not applied · 8 not met · 12 not assessed

Pathogenic

PS1 Not assessed: no alternate nucleotide change producing p.Pro12Arg was documented in the available evidence.

PS2 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: no reviewed functional study directly tested MEN1 p.Pro12Arg, while same-codon p.Pro12Leu results cannot establish PS3 for p.Pro12Arg.

PS4 Not assessed: no exact-variant case-control counts or statistically significant phenotype-enrichment metric is available.

PM1 Not assessed: no authoritative MEN1 critical-domain boundary or significant hotspot was available for residue 12.

PM6 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: no affected relatives, variant-positive family members, or informative meioses are documented for segregation analysis.

PP2 Not met: missense variants comprise approximately 10% of reported MEN1 mutations, so missense is not the predominant disease mechanism.

PP4 Not assessed: no patient-specific, highly specific MEN1 phenotype or family history is documented.

PP5 Not met: zero ClinVar expert-panel submissions exist for this exact variant, despite four Likely pathogenic laboratory records.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of 0.05.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BS1 allele-frequency threshold of 0.01.

BS2 Not met: no healthy-individual or homozygote observation is reported; population databases instead report the variant as absent.

BS3 Not assessed: no reviewed assay directly demonstrated normal function for MEN1 p.Pro12Arg, and other MEN1 substitutions cannot establish BS3 for this variant.

BS4 Not assessed: no unaffected variant-positive relatives or phenotype-based non-segregation observations are documented.

BP1 Not met: MEN1 includes disease-associated missense variants, including same-residue P12L with impaired menin-RPA2 binding.

BP2 Not assessed: no affected-proband genotype, cis/trans phase, or co-occurring pathogenic/benign allele is documented.

BP4 Not met: REVEL 0.879 exceeds the most permissive <=0.29 supporting BP4 threshold for benign computational evidence.

BP5 Not assessed: no patient-level evidence shows an alternative molecular diagnosis explaining the relevant phenotype.

BP6 Not met: zero ClinVar expert-panel submissions provide an exact-variant Benign or Likely benign classification.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories). (ClinVarID = 1733068)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.879. BayesDel score = 0.561369.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MEN1, a transcriptional repressor, is altered by mutation and deletion in various cancer types, including parathyroid and endocrine cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

12509449 ↗ The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

11739416 ↗ Guidelines for diagnosis and therapy of MEN type 1 and type 2. CLINVAR

15254225 ↗ Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway. CLINVAR

21264250 ↗ The menin tumor suppressor protein is phosphorylated in response to DNA damage. CLINVAR

21819486 ↗ Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. CLINVAR

22090276 ↗ Menin missense mutants encoded by the MEN1 gene that are targeted to the proteasome: restoration of expression and activity by CHIP siRNA. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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