No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MEN1 encodes menin, a tumor suppressor protein that helps control gene activity by modifying chromatin structure and histones. Loss of menin function causes multiple endocrine neoplasia type 1 (MEN1 syndrome), an inherited disorder marked by tumors of the pituitary, parathyroid, and pancreas. Menin interacts with several proteins that regulate cell growth and division, and its loss contributes to both inherited and sporadic endocrine tumors.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (supporting): extremely rare in gnomAD v4.1, 23 of 1,613,754 alleles (0.0014%), below the 0.1% threshold.
Met (supporting): SpliceAI maximum delta 0.00, below the <0.10 BP4 threshold.
VUS: the only met criteria conflict, PM2 (supporting, toward pathogenic) and BP4 (supporting, toward benign), so no ACMG/AMP classification threshold is reached. No MEN1-specific interpretation framework exists, so generic ACMG/AMP thresholds were applied.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 23 / 1,613,754 alleles. Recorded AF 1.42525e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.59543e-05; MAF= 0.00160%, 4/250716 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.53519e-05; MAF= 0.00354%, 4/113148 alleles, homozygotes = 0); grpmax FAF= 1.126e-05.
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
6 Likely benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 11 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No MEN1-specific CSPEC/VCEP framework was available; generic ACMG/AMP population rules were therefore used.
Population data show an extremely rare synonymous variant with 0 homozygotes, but the observed allele count is incompatible with BA1 or BS1 and does not establish BS2.
PM2 is retained at supporting strength because the frequency is below the generic rare-variant threshold, with an explicit caveat that the variant is observed rather than strictly absent in gnomAD.
No criteria match.
PM2 is met at supporting strength. The variant is extremely rare in population databases: gnomAD v4.1 shows 23/1,613,754 alleles (AF 1.42525e-05; maximum subpopulation AF 1.94928e-05), gnomAD v2.1 shows 4/250,716 alleles (AF 1.59543e-05; maximum subpopulation AF 3.53519e-05), and gnomAD-Canada reports absence. There are 0 homozygotes in both gnomAD datasets. The variant is not completely absent from gnomAD, so full absent-variant PM2 is not warranted; under the generic operating threshold used here, AF <0.1% supports PM2. No MEN1-specific VCEP rule or penetrance/prevalence-adjusted threshold was available.
Generic ACMG/AMP PM2 rule with the available operating calibration: an absent or extremely rare variant in population databases may support PM2; use AF <0.1% for supporting strength, while documenting that a nonzero allele count is not strict absence.
MEN1 NM_001370259.2:c.300C>G is synonymous (p.Ala100=). SpliceAI maximum delta is 0.00, which is below the generic non-missense BP4 threshold of <0.10. BP4 is met at supporting strength; this uses the same splice-prediction evidence as PP3 and is not double-counted.
Generic ACMG/AMP fallback: for a synonymous/non-missense variant, use SpliceAI only; BP4_supporting requires maximum delta <0.10.
MEN1 NM_001370259.2:c.300C>G is synonymous (p.Ala100=), so the generic non-missense splice-prediction path applies. SpliceAI maximum delta is 0.00, below the generic PP3 threshold of >0.20; PP3 is therefore not met.
Generic ACMG/AMP fallback: for a synonymous/non-missense variant, use SpliceAI only; PP3_supporting requires maximum delta >0.20.
PP5 is not applicable because ClinVar has no exact-variant pathogenic or likely pathogenic expert-panel assertion.
This assessment applies PP5 only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion.
BA1 is not met. The highest reported population frequency is 1.42525e-05 overall in gnomAD v4.1 and 1.94928e-05 in the highest-frequency subpopulation, European (non-Finnish), far below the generic benign allele-frequency threshold of >1%. The variant is also absent from gnomAD-Canada v1.0.
Generic ACMG/AMP benign frequency rule: BA1 requires an allele frequency greater than 1% in a population database; apply the highest credible ancestry-specific frequency.
BS1 is not met. The highest observed frequency is 1.94928e-05 in gnomAD v4.1 European (non-Finnish) individuals and 3.53519e-05 in gnomAD v2.1 European (non-Finnish) individuals, both far below the generic operating threshold of >0.3% for a frequency greater than expected for a pathogenic MEN1 variant. No disease-specific penetrance- or prevalence-adjusted threshold was available to justify a different cutoff.
Generic ACMG/AMP BS1 frequency rule: apply when the allele frequency is greater than expected for the disorder; in this generic operating framework, use >0.3% and evaluate the highest credible ancestry-specific frequency.
BS2 is not met. gnomAD v2.1 and v4.1 each report 0 homozygotes for the variant. No source documents the variant in healthy adult homozygotes, and the available population data do not provide the observation required for BS2.
Generic ACMG/AMP BS2 rule: requires observation of the variant in healthy adults, typically as homozygotes for a recessive disorder or heterozygotes/homozygotes as appropriate for the disease mechanism; absence of homozygotes is not itself BS2 evidence.
BP6 is not applicable because ClinVar has no exact-variant benign or likely benign expert-panel assertion.
This assessment applies BP6 only to an exact-variant ClinVar expert-panel Benign or Likely benign assertion.
No proband-level de novo evidence is available in the case bundle. There is no documented parental testing showing the variant absent in both unaffected parents, no maternity/paternity confirmation, and no phenotype-specific de novo observation to evaluate.
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed; stronger application requires appropriate phenotype and, where applicable, multiple observations. No applicable MEN1-specific specification was found.
No validated, variant-specific functional assay demonstrating a damaging effect was identified for NM_001370259.2:c.300C>G (p.Ala100=). The available functional-themed publication is the general ACMG/AMP standards paper and does not report this variant or a MEN1 assay; therefore PS3 cannot be applied.
No case-control data or other quantitative enrichment data for the exact MEN1 c.300C>G (p.Ala100=) variant were identified in the supplied evidence.
Generic ACMG/AMP PS4: prevalence of the variant in affected individuals must be significantly increased relative to controls.
No assumed de novo evidence is available. The case bundle does not report parental testing, a de novo event without confirmed maternity/paternity, or a compatible proband phenotype.
Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease and no family history, without confirmation of maternity and/or paternity. No applicable MEN1-specific specification was found.
No affected relatives, informative meioses, variant-positive relatives, or phenotype-consistent segregation data are reported. Therefore, segregation cannot be evaluated at supporting, moderate, or strong strength.
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength may be increased with sufficient informative meioses under an applicable validated framework. No applicable MEN1-specific specification was found.
No proband phenotype, clinical diagnostic findings, or phenotype-to-gene differential assessment is present for this case; therefore phenotype specificity cannot be evaluated.
Generic ACMG/AMP PP4: the patient's phenotype or family history must be highly specific for a disease with a single genetic etiology.
No validated, variant-specific functional assay demonstrating preserved MEN1 function was identified for NM_001370259.2:c.300C>G (p.Ala100=). The available functional-themed publication is a general ACMG/AMP standards paper without a MEN1 assay or result for this variant; therefore BS3 cannot be applied.
No affected family members tested for the variant are documented as lacking the variant. In the absence of an informative pedigree and phenotype-confirmed relatives, non-segregation cannot be established.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family. Application requires informative affected relatives and reliable phenotype/genotype data. No applicable MEN1-specific specification was found.
No reliable phase or family-genotype evidence is available to determine whether NM_001370259.2:c.300C>G (p.Ala100=) occurs in trans with a pathogenic MEN1 variant or in cis with a pathogenic variant. The variant-specific literature extraction does not report such an observation.
Generic ACMG/AMP BP2: consider when the variant is observed in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant for any disorder; phase and pathogenicity of the comparator must be established.
No patient-level evidence identifies an alternate molecular diagnosis that fully explains a presenting phenotype.
Generic ACMG/AMP BP5: a variant is found in a case with an alternate molecular basis for disease.
The variant is synonymous and SpliceAI predicts no splice effect (maximum delta 0.00), satisfying the splice-prediction component of generic BP7. However, no nucleotide-conservation evidence was provided to establish that the affected nucleotide is not highly conserved, so BP7 cannot be assessed as met.
Generic ACMG/AMP BP7: synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
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_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). 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.
deterministic_prefilter: requires_null_variant_class
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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.
deterministic_prefilter: requires_missense
MEN1 is documented in this case as an autosomal-dominant disorder context, whereas PM3 is the recessive allelic evidence criterion. No recessive inheritance context or affected proband with this variant in trans with a pathogenic MEN1 variant is provided.
Generic ACMG/AMP PM3: apply only when the variant is observed in trans with a pathogenic variant in a recessive disorder; not applicable in the documented autosomal-dominant MEN1 context.
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_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). 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.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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.
deterministic_prefilter: requires_missense
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001370259.2:c.300C>G in MEN1 is a synonymous (silent) substitution predicted to produce NP_001357188.2:p.(Ala100=). 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.
deterministic_prefilter: requires_repeat_region_indel
Every interpreted variant in MEN1, mapped onto the exon structure of NM_001370259.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)23 / 1,179,924 | 1.9e-05 |
| European (non-Finnish)4 / 113,148 | 3.5e-05 |
This variant is present in gnomAD v4.1 (AF= 1.42525e-05; MAF= 0.00143%, 23/1613754 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.94928e-05; MAF= 0.00195%, 23/1179924 alleles, homozygotes = 0); grpmax FAF= 1.298e-05.
This variant is present in gnomAD v2.1 (AF= 1.59543e-05; MAF= 0.00160%, 4/250716 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.53519e-05; MAF= 0.00354%, 4/113148 alleles, homozygotes = 0); grpmax FAF= 1.126e-05.
Absent from gnomAD-Canada v1.0.
MEN1 NM_001370259.2:c.300C>G is synonymous (p.Ala100=). SpliceAI maximum delta is 0.00, which is below the generic non-missense BP4 threshold of <0.10. BP4 is met at supporting strength; this uses the same splice-prediction evidence as PP3 and is not double-counted.
Generic ACMG/AMP fallback: for a synonymous/non-missense variant, use SpliceAI only; BP4_supporting requires maximum delta <0.10.
MEN1 NM_001370259.2:c.300C>G is synonymous (p.Ala100=), so the generic non-missense splice-prediction path applies. SpliceAI maximum delta is 0.00, below the generic PP3 threshold of >0.20; PP3 is therefore not met.
Generic ACMG/AMP fallback: for a synonymous/non-missense variant, use SpliceAI only; PP3_supporting requires maximum delta >0.20.
The variant is synonymous and SpliceAI predicts no splice effect (maximum delta 0.00), satisfying the splice-prediction component of generic BP7. However, no nucleotide-conservation evidence was provided to establish that the affected nucleotide is not highly conserved, so BP7 cannot be assessed as met.
Generic ACMG/AMP BP7: synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
7 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Location Proposed Criteria for Interpretation of Sequence Variants
Context ACMG/AMP/CAP workgroup consensus, laboratory surveys, workshop feedback, and review of existing variant-classification guidance; no MEN1-specific cohort or functional assay for this variant is described.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 1.42525e-05; MAF= 0.00143%, 23/1613754 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.94928e-05; MAF= 0.00195%, 23/1179924 alleles, homozygotes = 0); grpmax FAF= 1.298e-05.
This variant is present in gnomAD v2.1 (AF= 1.59543e-05; MAF= 0.00160%, 4/250716 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.53519e-05; MAF= 0.00354%, 4/113148 alleles, homozygotes = 0); grpmax FAF= 1.126e-05.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 457319)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.