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 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.
Met at moderate strength: disease-associated P12L at the same residue impaired menin-RPA2 binding in a yeast two-hybrid assay.
Met at moderate strength: REVEL 0.879 exceeds the >=0.773 moderate PP3 threshold but is below the >=0.932 strong threshold.
No benign criterion marked as applied in the recorded assessment.
VUS: PM5 (moderate), PP3 (moderate), and PM2 (supporting) provide two moderate and one supporting criterion, below generic ACMG thresholds for Likely Pathogenic or Pathogenic.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.879. Refer to the recorded PP3/BP4 rationale for interpretation.
4 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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.
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: 3 met · 8 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No MEN1-specific VCEP or gene-specific framework was available, so generic ACMG/AMP criterion concepts were used.
PS4, PP4, and BP5 remain not assessed because the available records lack the required quantitative enrichment or patient-level phenotype/alternative-cause evidence.
PP5 and BP6 are not met because the exact variant has zero ClinVar expert-panel submissions; the available records are single-submitter clinical-laboratory assertions.
No applicable MEN1-specific VCEP or gene-specific framework was available, so the supplied generic ACMG/AMP and ClinGen-SVI population rules were used.
The exact variant is absent from gnomAD v2.1, gnomAD v4.1, and the available gnomAD non-cancer subsets; this supports PM2 at supporting strength but does not support BA1, BS1, or BS2.
No criteria match.
PM2 is met at supporting strength. The exact variant NM_000244.3:c.35C>G (MEN1 p.Pro12Arg) is absent from gnomAD v2.1 and gnomAD v4.1. It is also absent from the available gnomAD v2.1 non-cancer exome-only subset and gnomAD v3.1 non-cancer genomes-only subset. With no applicable MEN1-specific VCEP specification, the supplied generic PM2 threshold of allele frequency <=0.0001 applies; the observed frequency is effectively 0 in each queried dataset.
Generic ACMG/ClinGen-SVI PM2: rare or absent from population databases, applied at supporting strength when allele frequency <=0.0001; no MEN1-specific VCEP framework was available.
PMID:12509449 identifies P12L as a disease-associated MEN1 missense mutation at the same residue and reports impaired menin-RPA2 binding in a yeast two-hybrid assay. P12L is a different missense substitution from the queried p.Pro12Arg and provides same-residue pathogenic evidence supporting classic PM5 at moderate strength; the functional result is not being treated as a direct assay of P12R.
PM5: novel missense change at an amino-acid residue where a different missense change is established as pathogenic; classic generic strength is moderate.
The variant is a missense substitution, NM_000244.3:c.35C>G (p.Pro12Arg), so PP3 is evaluated using the missense REVEL path only. REVEL is 0.879, which meets the calibrated moderate PP3 threshold of >=0.773 but not the strong threshold of >=0.932. This threshold is from the ClinGen SVI REVEL calibration by Pejaver et al. (2022), PMID:36413997. SpliceAI and BayesDel were not used for this criterion because the variant is missense and no governing VCEP specification is available.
For a missense variant, apply REVEL only; PP3 moderate applies at REVEL >=0.773 and strong at >=0.932, using Pejaver et al. 2022 (PMID:36413997).
PP2 is not supported because the MEN1 literature describes missense variants as a minority of germline mutations, approximately 10%, while most reported mutations are nonsense, deletions, or insertions. This does not support a gene-level pattern of unusually rare benign missense variation together with missense as the predominant disease mechanism.
PP2: missense variants are a common disease mechanism in the gene and benign missense variation is unusually rare.
PP5 is not met because the exact variant has zero ClinVar expert-panel submissions. The four exact-variant records are single-submitter clinical-laboratory Likely pathogenic assertions; ordinary laboratory submissions and the aggregate ClinVar label do not qualify for PP5.
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; non-expert submissions and aggregate labels do not qualify.
BA1 is not met. The exact variant NM_000244.3:c.35C>G (MEN1 p.Pro12Arg) is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is not at or above the generic stand-alone threshold of 0.05 from ACMG/AMP 2015 (PMID:25741868). The available non-cancer subsets also report the variant as absent; no population source supports a common allele frequency. No MEN1-specific VCEP specification was available, so the generic threshold applies.
Generic ACMG/AMP BA1: stand-alone benign evidence requires allele frequency >=0.05; no MEN1-specific VCEP framework was available.
BS1 is not met. The exact variant is absent from gnomAD v2.1 and gnomAD v4.1, and is also absent from the available non-cancer subsets, rather than occurring at a frequency greater than expected for MEN1. Therefore it does not meet the generic BS1 threshold of allele frequency >=0.01. No MEN1-specific VCEP specification was available.
Generic ACMG/AMP BS1: strong benign evidence requires allele frequency greater than expected for the disorder; supplied generic threshold >=0.01; no MEN1-specific VCEP framework was available.
BS2 is not met. The available population evidence shows the variant is absent from gnomAD v2.1, gnomAD v4.1, and the available non-cancer subsets; it provides no observation of the variant in healthy adults, including no homozygote observation. Absence from a population database is evidence for rarity and PM2, not positive BS2 evidence of occurrence in unaffected individuals.
Generic ACMG/AMP BS2 requires observation in healthy adults, including healthy homozygotes for a recessive disorder; no such observation is available.
BP1 is not met because, although MEN1 loss of function is an important disease mechanism, the literature also documents disease-associated missense variants, including P12L at the same residue as the queried variant, with impaired menin-RPA2 binding. Therefore missense variation in MEN1 cannot be treated as generally outside the established disease mechanism.
BP1: missense variants are generally not a known disease mechanism in a gene where truncating variants cause disease.
The variant is a missense substitution, NM_000244.3:c.35C>G (p.Pro12Arg), so BP4 is evaluated using the missense REVEL path only. REVEL is 0.879, which exceeds all calibrated benign BP4 cutoffs (supporting <=0.29, moderate <=0.183, and strong <=0.016); therefore BP4 is not met. This threshold set is from the ClinGen SVI REVEL calibration by Pejaver et al. (2022), PMID:36413997. The SpliceAI score was not substituted because a missense variant's splice prediction cannot establish BP4, and BayesDel has no applicable generic calibration.
For a missense variant, apply REVEL only; BP4 supporting applies at REVEL <=0.29, moderate at <=0.183, and strong at <=0.016, using Pejaver et al. 2022 (PMID:36413997).
BP6 is not met because the exact variant has zero ClinVar expert-panel submissions. The four exact-variant records are single-submitter clinical-laboratory Likely pathogenic assertions, with no expert-panel Benign or Likely benign classification; non-expert and aggregate records cannot trigger BP6.
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; non-expert submissions and aggregate labels do not qualify.
PS1 requires a previously reported pathogenic variant producing the same amino-acid change, p.Pro12Arg, through a different nucleotide change. The reviewed case evidence identifies the queried c.35C>G variant but does not document an alternate nucleotide change producing p.Pro12Arg. A systematic codon-level search for all alternate nucleotide representations was not available, so PS1 cannot be concluded from the available evidence.
PS1: same amino-acid change as a previously established pathogenic variant, caused by a different nucleotide change.
No case-level evidence documents that NM_000244.3:c.35C>G (p.Pro12Arg) arose de novo in the proband. The available records do not provide parental genotypes, confirmed parental relationship, maternity/paternity confirmation, or a clinically consistent phenotype assessment sufficient to apply PS2.
No applicable MEN1-specific VCEP specification was available, so generic ACMG/AMP functional-evidence principles were used. The variant is NM_000244.3:c.35C>G (NP_000235.2:p.Pro12Arg). The reviewed functional literature includes a same-codon P12L yeast two-hybrid interaction result and other MEN1 missense-mutant stability, phosphorylation, degradation, and transcriptional assays, but none directly tested P12R. Because PS3 requires a well-established functional study of the variant itself with interpretable controls and biologically relevant assay results, findings for P12L or other substitutions cannot be transferred to P12R. No validated assay result, assay control set, or quantitative functional measurement for P12R was identified; therefore PS3 cannot be applied at any strength.
No MEN1-specific VCEP framework was available. The case materials contain no exact-variant affected-case and control counts, odds ratio, likelihood ratio, or statistically significant phenotype-enrichment result for NM_000244.3:c.35C>G (p.Pro12Arg). The exact-variant ClinVar records are laboratory classifications, not case-control data, so PS4 cannot be assessed.
Generic PS4 requires statistically significant enrichment of the variant in affected individuals compared with appropriate controls; no applicable VCEP specification was available.
No MEN1-specific VCEP framework or authoritative domain table was available. The available evidence documents functional effects for another codon-12 substitution, P12L, but does not establish that residue 12 lies within a well-established critical functional domain or statistically supported mutational hotspot meeting PM1. The hotspot query returned no statistically significant hotspot, and no complete domain specification was available for review.
PM1: variant located in a well-established critical functional domain or hotspot without benign variation, using a governing specification when available.
No case-level evidence supports an assumed de novo occurrence of NM_000244.3:c.35C>G (p.Pro12Arg) without parental testing. The available records do not describe a proband with a phenotype consistent with MEN1 together with a documented negative family history and credible de novo inference.
No informative affected relatives, family members carrying NM_000244.3:c.35C>G (p.Pro12Arg), or documented meioses are reported. Consequently, there is no segregation dataset from which to assign PP1 strength.
No MEN1-specific VCEP framework was available. The case materials identify MEN1 and the variant but provide no patient-level phenotype, diagnostic features, or family history showing a phenotype highly specific for MEN1. General MEN1 clinical descriptions do not establish a phenotype for this individual, so PP4 cannot be assessed.
Generic PP4 requires a phenotype or family history highly specific for a disease with a single-gene etiology; no applicable VCEP specification was available.
No applicable MEN1-specific VCEP specification was available, so generic ACMG/AMP functional-evidence principles were used. BS3 requires a well-established functional study showing that the tested variant does not impair the relevant gene or protein function, with suitable controls and a biologically relevant assay. The reviewed MEN1 functional papers tested p.Pro12Leu or other substitutions, not p.Pro12Arg; their results neither demonstrate normal function nor provide a benign functional result for this variant. Consequently, there is no direct evidence supporting BS3, and BS3 cannot be applied at any strength.
No clinically evaluated unaffected relatives who carry NM_000244.3:c.35C>G (p.Pro12Arg) are documented. There is therefore no non-segregation observation that can support BS4, and the absence of family data cannot be treated as evidence against segregation.
No gene-specific VCEP specification was available. Generic BP2 for a dominant disorder requires documented phase showing the evaluated variant in trans with a pathogenic variant, or another qualifying allelic configuration under the applicable disease model. The case evidence provides no affected-proband genotype, second allele, cis/trans phase, or segregation result, so BP2 cannot be assessed.
No MEN1-specific VCEP framework was available. No patient-level case demonstrates that the relevant phenotype is explained by an alternative molecular cause, and no alternative pathogenic diagnosis is documented for a case involving this exact variant. Therefore the evidence is insufficient to assess BP5.
Generic BP5 requires the variant to be found in a case whose phenotype is explained by an alternative molecular cause; no applicable VCEP specification was available.
deterministic_prefilter: requires_null_variant_class
No gene-specific VCEP specification was available. Generic PM3 is intended for evidence of the evaluated variant in trans with a pathogenic variant in an affected individual with a recessive disorder. MEN1 is described as autosomal dominant, so a recessive biallelic PM3 assessment is not applicable to this disease context. The available evidence contains no affected-proband biallelic observation or phase data that would alter this inheritance-based determination.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
Every interpreted variant in MEN1, mapped onto the exon structure of NM_000244.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_000244.3:c.35C>G (p.Pro12Arg), so PP3 is evaluated using the missense REVEL path only. REVEL is 0.879, which meets the calibrated moderate PP3 threshold of >=0.773 but not the strong threshold of >=0.932. This threshold is from the ClinGen SVI REVEL calibration by Pejaver et al. (2022), PMID:36413997. SpliceAI and BayesDel were not used for this criterion because the variant is missense and no governing VCEP specification is available.
For a missense variant, apply REVEL only; PP3 moderate applies at REVEL >=0.773 and strong at >=0.932, using Pejaver et al. 2022 (PMID:36413997).
The variant is a missense substitution, NM_000244.3:c.35C>G (p.Pro12Arg), so BP4 is evaluated using the missense REVEL path only. REVEL is 0.879, which exceeds all calibrated benign BP4 cutoffs (supporting <=0.29, moderate <=0.183, and strong <=0.016); therefore BP4 is not met. This threshold set is from the ClinGen SVI REVEL calibration by Pejaver et al. (2022), PMID:36413997. The SpliceAI score was not substituted because a missense variant's splice prediction cannot establish BP4, and BayesDel has no applicable generic calibration.
For a missense variant, apply REVEL only; BP4 supporting applies at REVEL <=0.29, moderate at <=0.183, and strong at <=0.016, using Pejaver et al. 2022 (PMID:36413997).
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.879. BayesDel score = 0.561369.
9 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Of the 15 mutations tested, three (H139D, A160P, and A176P) abolished the interaction completely, eight (P12L, L22R, H139Y, F144V, F159C, L286P, A309P, and T344R) impaired binding to various degrees, and four (A164D, W183S, W436R, and F447S) had little or no effect.
Location Results, ‘Effect of disease-associated MEN1 missense mutations on menin-RPA2 interaction’; Table 3
Context Gal4-based yeast two-hybrid assay measuring interaction between wild-type or mutant menin and RPA2; 15 disease-associated MEN1 missense mutations were tested.
MEN1 mutations are scattered in and around the open reading frame of menin and are diverse in their types; approximately 25% are nonsense, approximately 45% are small deletions, approximately 15% are small insertions, less than 5% are donor-splice mutations, and approximately 10% are missense mutations, predicted to change one to three amino acids in menin (1, 8, 10, 62–64).
Section: ‘Screening of DNA OR of tumor expressions in diagnosis of the MEN1 carrier,’ page 5662
all of the MEN1 mutants tested for this study were expressed at extremely low levels compared to the WT protein
Results, ‘MEN1 disease-associated single amino acid mutations reduce the stability of menin protein,’ and Figures 1–4
As shown in Figure 6A, the mutants P12L, L22R, and A309P fail to achieve the level of Ser394 phosphorylation that is observed in the wild type menin and the H139D and A242Vmutants.
Results, ‘MEN1-associated missense menin mutants show altered Ser394 and Ser487 phosphorylation,’ paragraph 1; Figure 6A
All tested mutants associated with typical MEN1 showed reduced stability. Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1.
Abstract; Results, ‘Steady-state expression levels of variant menin proteins’ and ‘Repression of JunD-mediated transactivation by variant menin’
Almost without exception, the menin mutants were expressed at markedly reduced levels relative to WT menin and were targeted to the proteasome and rapidly degraded.
Discussion, final section; Results sections on menin missense mutant degradation and CHIP siRNA rescue
Multiple endocrine neoplasia type 1 131100 20301710 Child/adult MEN1 613733 AD KP and EP
Table 1, Conditions, genes, and variants recommended for return of incidental findings in clinical sequencing
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.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories). (ClinVarID = 1733068)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.879. BayesDel score = 0.561369.
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.
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.