Classification rationale

BS1BP7 Likely Benign

MEN1 c.1311G>A

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.¹ 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.² SpliceAI predicts no significant splice impact for this synonymous change, with a maximum delta score of 0.08, supporting a benign computational interpretation.³

BS1 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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 · 2 applied · 16 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 · 2

Strength Supporting Moderate Strong Very strong

BS1 strong review Benign

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%.

gnomAD v2.1 total AF 0.00111824highest subpopulation AF 0.00260618.gnomAD v4.1 total AF 0.00145029

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting review Benign

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.

Protein consequence is p.(Leu437=) / p.(L437=).SpliceAI max delta score 0.08.

spliceai ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with parental testing was identified.

PS3 No well-established functional study showing a damaging effect of this exact variant was identified.

PS4 Available evidence does not show enrichment of this variant in affected individuals versus controls.

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.

PM2 Population frequency is above the PM2 threshold.

PM6 No apparent de novo occurrence without confirmed parentage was identified.

PP1 No segregation data were identified for this exact variant.

PP3 Available computational evidence does not support a damaging splicing effect.

PP4 No case-specific phenotype information was provided to determine whether the clinical presentation is highly specific for MEN1 caused by this variant.

Benign

BA1 Population frequency does not reach the BA1 threshold.

BS2 Population observations alone were not considered sufficient to establish this criterion for a dominant, age-related tumor predisposition condition.

BS3 No well-established functional study showing a benign effect of this exact variant was identified.

BS4 No nonsegregation data were identified for this exact variant.

BP2 No phase data or co-occurrence data were identified.

BP3 No evidence was identified that this variant lies in a repetitive region without a known function.

BP5 No evidence was identified for an alternate molecular cause explaining the phenotype.

N/A · 10 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP4 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

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.

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.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.15% · 2341 / 1,614,160
5 hom · FAF 0.33%

Amish 6 / 912	0.66%
Middle Eastern 28 / 6,054	0.46% 1 hom
Ashkenazi Jewish 64 / 29,606	0.22%
European (non-Finnish) 1987 / 1,180,024	0.17% 3 hom
Remaining individuals 93 / 62,504	0.15% 1 hom
Admixed American 60 / 60,022	0.1%
South Asian 58 / 91,090	0.064%
African/African American 39 / 75,064	0.052%
European (Finnish) 6 / 63,998	0.0094%

+ 1 not observed (East Asian)

gnomAD v2.1

0.11% · 316 / 282,586
1 hom · FAF 0.15%

Ashkenazi Jewish 27 / 10,360	0.26%
Remaining individuals 14 / 7,220	0.19% 1 hom
European (non-Finnish) 206 / 128,986	0.16%
Admixed American 37 / 35,412	0.1%
African/African American 14 / 24,948	0.056%
South Asian 16 / 30,616	0.052%
European (Finnish) 2 / 25,094	0.008%

+ 1 not observed (East Asian)

gnomAD v4 ↗ gnomAD v2 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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 ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

10617276 ↗ Molecular pathology of multiple endocrine neoplasia type I: two novel germline mutations and updated classification of mutations affecting MEN1 gene. CLINVAR

11524904 ↗ 10 Swiss kindreds with multiple endocrine neoplasia type 1: assessment of screening methods. CLINVAR

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

15464422 ↗ Genetic screening methods for the detection of mutations responsible for multiple endocrine neoplasia type 1. CLINVAR

17879353 ↗ Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. CLINVAR

17953629 ↗ MEN1 gene mutations in Hungarian patients with multiple endocrine neoplasia type 1. CLINVAR

20833329 ↗ Multiple endocrine neoplasia type 1 (MEN1). CLINVAR

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. CLINVAR

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

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