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 ↗

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

MEN1 NM_000244.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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