About MEN1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MEN1 c.1311G>A, p.(Leu437=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
Population frequency is above the BS1 threshold. This variant is present at 0.14503% overall in gnomAD v4.1, with a highest observed population frequency of 0.65789% in Amish individuals, which is above the non-VCEP BS1 threshold of 0.3%.
BP7Supporting
BP7 · supporting
This is a synonymous variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.08, supporting no significant impact on RNA splicing.
Recorded classification: Likely benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong benign, BP7 supporting benign; combination = no applied criteria, which maps to Likely Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
2,341 / 1,614,160 alleles
gnomAD v4.1: 2,341 / 1,614,160 alleles. Recorded AF 0.00145029. Recorded homozygote count 5.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00111824; MAF= 0.11182%, 316/282586 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00260618; MAF= 0.26062%, 27/10360 alleles, homozygotes = 0); grpmax FAF= 0.00146114.
SpliceAI score
0.080 maximum delta
Recorded SpliceAI maximum delta score: 0.080. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
18 reported laboratory submissions
10 Likely benign · 7 Benign · 1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MEN1 NM_000244.3:c.1311G>A (NP_000235.2:p.(Leu437=); NP_000235.2:p.(L437=)) variant has been reported in ClinVar predominantly as likely benign or benign, with 10 likely benign, 7 benign, and 1 uncertain significance submissions.
This variant is present in gnomAD at 0.11182% in v2.1 and 0.14503% in v4.1, with a highest observed population frequency of 0.65789% in Amish individuals in v4.1, which is above the 0.3% BS1 threshold and argues against a rare pathogenic MEN1 variant.
SpliceAI predicts no significant splice impact for this synonymous change, with a maximum delta score of 0.08, supporting a benign computational interpretation.
No criteria match.
Met · 2
BS1 StrongPopulation frequency is above the BS1 threshold. This variant is present at 0.14503% overall in gnomAD v4.1, with a highest observed population frequency of 0.65789% in Amish individuals, which is above the non-VCEP BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 0.00111824
- highest subpopulation AF 0.00260618.
- gnomAD v4.1 total AF 0.00145029
- highest subpopulation AF 0.00657895.
Sources
BP7 SupportingThis is a synonymous variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.08, supporting no significant impact on RNA splicing. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Leu437=) / p.(L437=).
- SpliceAI max delta score 0.08.
Still missing
- No direct RNA study for this exact variant was identified.
Sources
Not met · 5 · evaluated, threshold not reached
PS4 Available evidence does not show enrichment of this variant in affected individuals versus controls. The variant is also present in population databases at frequencies not consistent with a rare pathogenic MEN1 variant. Details ▾Hide ▴
Evidence considered
- ClinVar contains predominantly benign/likely benign submissions rather than a pathogenic case series.
- gnomAD shows recurrent population observations.
Still missing
- No case-control study or clear affected-case count for this exact variant was identified.
Sources
PM1 This variant does not lie in a statistically significant hotspot, and no critical benign-variation-depleted region at this residue was identified from the available evidence. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review reported no hotspot row for MEN1 L437.
Still missing
- No independent domain-specific evidence establishing codon 437 as a critical hotspot was identified.
Sources
PM2 Population frequency is above the PM2 threshold. The variant is present at 0.11182% in gnomAD v2.1 and 0.14503% in gnomAD v4.1, both above the non-VCEP PM2 threshold of 0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 0.00111824.
- gnomAD v4.1 total AF 0.00145029.
Sources
PP3 Available computational evidence does not support a damaging splicing effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.08. Details ▾Hide ▴
Evidence considered
- SpliceAI scores: DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.08
- DS_DL 0.01
- max delta 0.08.
Still missing
- REVEL and BayesDel were not available for this synonymous change
- and no direct RNA study was identified.
Sources
BA1 Population frequency does not reach the BA1 threshold. The highest observed population frequency in gnomAD v4.1 is 0.65789%, which is below the non-VCEP BA1 threshold of 1%. Details ▾Hide ▴
Not assessed · 11 · no assessment recorded
PS2 No confirmed de novo occurrence with parental testing was identified. Details ▾Hide ▴
Still missing
- No trio-tested case report or submitter note documenting de novo occurrence was identified.
PS3 No well-established functional study showing a damaging effect of this exact variant was identified. Details ▾Hide ▴
Still missing
- No variant-specific RNA or functional assay demonstrating an abnormal effect was identified.
PM6 No apparent de novo occurrence without confirmed parentage was identified. Details ▾Hide ▴
Still missing
- No simplex case report or submitter note describing this exact variant as apparently de novo was identified.
PP1 No segregation data were identified for this exact variant. Details ▾Hide ▴
Still missing
- No pedigree or family cosegregation report was identified.
PP4 No case-specific phenotype information was provided to determine whether the clinical presentation is highly specific for MEN1 caused by this variant. Details ▾Hide ▴
Still missing
- No individual phenotype or family history details were available for PP4 review.
BS2 Population observations alone were not considered sufficient to establish this criterion for a dominant, age-related tumor predisposition condition. Details ▾Hide ▴
Evidence considered
- gnomAD reports 1 homozygote in v2.1 and 5 homozygotes in v4.1
- but without phenotype correlation.
Still missing
- No evidence was identified showing the variant in well-evaluated unaffected adult individuals with phenotype data.
Sources
BS3 No well-established functional study showing a benign effect of this exact variant was identified. Details ▾Hide ▴
Still missing
- No variant-specific RNA or functional assay demonstrating normal splicing or no functional impact was identified.
BS4 No nonsegregation data were identified for this exact variant. Details ▾Hide ▴
Still missing
- No pedigree showing lack of segregation with disease was identified.
BP2 No phase data or co-occurrence data were identified. Details ▾Hide ▴
Still missing
- No confirmed in-trans or in-cis observations were identified.
BP3 No evidence was identified that this variant lies in a repetitive region without a known function. Details ▾Hide ▴
Still missing
- No repeat-region annotation was identified.
BP5 No evidence was identified for an alternate molecular cause explaining the phenotype. Details ▾Hide ▴
Still missing
- No case-level alternate diagnosis data were available.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a synonymous variant, and the generic PVS1 review did not place it in a null-variant category eligible for PVS1. Available evidence does not show that this change creates a canonical splice-site alteration or another established loss-of-function effect. Details ▾Hide ▴
Evidence considered
- MEN1 loss of function is an established disease mechanism at the gene level.
- The variant-specific generic PVS1 scaffold did not support PVS1 application for this synonymous change.
Still missing
- No direct RNA study for this exact variant was identified.
Sources
PS1 N/APS1 is not applicable because this variant does not produce an amino acid substitution. Details ▾Hide ▴
Evidence considered
- Protein consequence is synonymous: p.(Leu437=) / p.(L437=).
PM3 N/APM3 is not applicable because this criterion is used for recessive disorders with trans observations, and MEN1 is not being evaluated under a recessive framework here. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 is not applicable because this variant does not change protein length. Details ▾Hide ▴
Evidence considered
- Protein consequence is synonymous.
PM5 N/APM5 is not applicable because this variant is not a missense change, and the PM5 candidate review did not support classic same-residue PM5 use for this variant. Details ▾Hide ▴
Evidence considered
- PM5 candidate artifact marked the variant as not eligible for classic same-residue PM5 logic.
Sources
pm5_candidates
PP2 N/APP2 is not applicable because this variant is not a missense change. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APP5 was not applied because a pathogenic assertion from an external source without independently reviewable evidence was not used for this interpretation. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 is not applicable because this variant is not a missense change. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 was not separately applied because this is a synonymous variant and BP7 is the more specific benign computational criterion for this context. Details ▾Hide ▴
BP6 N/ABP6 was not applied because benign assertions from external databases were not used as a standalone criterion without independent evidence review. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MEN1
- Transcript
- NM_000244.3
- Coding (HGVS c.)
- NM_000244.3:c.1311G>A
- Protein (HGVS p.)
- NP_000235.2:p.(Leu437=)
- GRCh38
- chr11:64805088 C>T
- GRCh37
- chr11:64572560 C>T
- ClinVar
- 4053813, 36524
Gene diagram
Every interpreted variant in MEN1, mapped onto the exon structure of NM_000244.3. Select a row to find it on the plot.
MEN1NM_000244.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MEN1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2,341 / 1,614,160 alleles
AF 0.00145 · 5 homozygotes · FAF 0.00329
gnomAD v2.1
316 / 282,586 alleles
AF 0.00112 · 1 homozygotes · FAF 0.00146
By genetic ancestry
gnomAD v4.1
AF 0.0015 · 2341 / 1,614,160 alleles · 5 hom · FAF 0.0033
| Amish6 / 912 | 0.0066 |
| Middle Eastern28 / 6,054 | 0.00461 hom |
| Ashkenazi Jewish64 / 29,606 | 0.0022 |
| European (non-Finnish)1987 / 1,180,024 | 0.00173 hom |
| Remaining individuals93 / 62,504 | 0.00151 hom |
| Admixed American60 / 60,022 | 0.001 |
| South Asian58 / 91,090 | 0.00064 |
| African/African American39 / 75,064 | 0.00052 |
| European (Finnish)6 / 63,998 | 9.4e-05 |
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD v2.1
AF 0.0011 · 316 / 282,586 alleles · 1 hom · FAF 0.0015
| Ashkenazi Jewish27 / 10,360 | 0.0026 |
| Remaining individuals14 / 7,220 | 0.00191 hom |
| European (non-Finnish)206 / 128,986 | 0.0016 |
| Admixed American37 / 35,412 | 0.001 |
| African/African American14 / 24,948 | 0.00056 |
| South Asian16 / 30,616 | 0.00052 |
| European (Finnish)2 / 25,094 | 8e-05 |
0 alternate alleles recorded in 1 other group: East Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00145029; MAF= 0.14503%, 2341/1614160 alleles, homozygotes = 5) and has highest observed frequency in the Amish population (AF= 0.00657895; MAF= 0.65789%, 6/912 alleles, homozygotes = 0); grpmax FAF= 0.00328643.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00111824; MAF= 0.11182%, 316/282586 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00260618; MAF= 0.26062%, 27/10360 alleles, homozygotes = 0); grpmax FAF= 0.00146114.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis is a synonymous variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.08, supporting no significant impact on RNA splicing. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Leu437=) / p.(L437=).
- SpliceAI max delta score 0.08.
Still missing
- No direct RNA study for this exact variant was identified.
Sources
PP3 Available computational evidence does not support a damaging splicing effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.08. Details ▾Hide ▴
Evidence considered
- SpliceAI scores: DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.08
- DS_DL 0.01
- max delta 0.08.
Still missing
- REVEL and BayesDel were not available for this synonymous change
- and no direct RNA study was identified.
Sources
BP4 N/ABP4 was not separately applied because this is a synonymous variant and BP7 is the more specific benign computational criterion for this context. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 10617276 ↗Molecular pathology of multiple endocrine neoplasia type I: two novel germline mutations and updated classification of mutations affecting MEN1 gene.No paper-specific finding is recorded.
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PMID 11524904 ↗10 Swiss kindreds with multiple endocrine neoplasia type 1: assessment of screening methods.Clerici T et al. · 2001No paper-specific finding is recorded.
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PMID 11739416 ↗Guidelines for diagnosis and therapy of MEN type 1 and type 2.No paper-specific finding is recorded.
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PMID 15464422 ↗Genetic screening methods for the detection of mutations responsible for multiple endocrine neoplasia type 1.No paper-specific finding is recorded.
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PMID 17879353 ↗Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.Lemos MC et al. · 2008No paper-specific finding is recorded.
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PMID 17953629 ↗MEN1 gene mutations in Hungarian patients with multiple endocrine neoplasia type 1.No paper-specific finding is recorded.
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PMID 20833329 ↗Multiple endocrine neoplasia type 1 (MEN1).No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2,341 / 1,614,160 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.080
Open source ↗
ClinVar
10 Likely benign · 7 Benign · 1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/36524/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-64572560-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-64805088-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000244.3%3Ac.1311…
- OncoKB ↗www.oncokb.org/gene/MEN1/L437=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MEN1+c.1311G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00145029; MAF= 0.14503%, 2341/1614160 alleles, homozygotes = 5) and has highest observed frequency in the Amish population (AF= 0.00657895; MAF= 0.65789%, 6/912 alleles, homozygotes = 0); grpmax FAF= 0.00328643.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00111824; MAF= 0.11182%, 316/282586 alleles, homozygotes = 1) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00260618; MAF= 0.26062%, 27/10360 alleles, homozygotes = 0); grpmax FAF= 0.00146114.
ClinVar
This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Benign (7 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 36524)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.