Classification rationale

PM2 BP4 VUS

MEN1 c.300C>G synonymous · exon 2

PM2 (Supporting): gnomAD v4.1 allele frequency 0.0014% (23 of 1,613,754 alleles), below the <0.1% threshold for extreme rarity. BP4 (Supporting): SpliceAI maximum delta 0.00, below the <0.10 threshold, predicting no splice effect. VUS overall: PM2 and BP4 are both supporting-strength but point in opposite directions, and this conflicting combination meets no ACMG/AMP pathogenic or benign threshold.

PM2 + BP4 → VUS

Gene diagram · NM_001370259.2 · variants mapped to exon structure

MEN1 NM_001370259.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 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

PM2 supporting Pathogenic

Met (supporting): extremely rare in gnomAD v4.1, 23 of 1,613,754 alleles (0.0014%), below the 0.1% threshold.

gnomAD v4.1 reports 23/1,613,754 alleles, AF 1.42525e-05, maximum subpopulation AF 1.94928e-05, and 0 homozygotes.gnomAD v2.1 reports 4/250,716 alleles, AF 1.59543e-05, maximum subpopulation AF 3.53519e-05, and 0 homozygotes.gnomAD-Canada v1.0 reports the variant as absent.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

BP4 supporting Benign

Met (supporting): SpliceAI maximum delta 0.00, below the <0.10 BP4 threshold.

No MEN1 VCEP/CSPEC or local gene-specific computational-evidence rule was retrieved; the generic ACMG/AMP fallback is governing.The case SpliceAI result for NM_001370259.2:c.300C>G has maximum delta score 0.00. The supplied generic non-missense rule assigns BP4_supporting when SpliceAI maximum delta is <0.10.This is a synonymous, not missense, variant; the generic rule directs use of SpliceAI only for this path. No independent missense-predictor evidence is added.

spliceai ↗PMID:25741868 ↗

Assessed · not applied · 6 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no parental testing or other de novo evidence was available.

PS3 Not assessed: no validated variant-specific functional assay showing a damaging effect was available.

PS4 Not assessed: no case-control or enrichment data for this exact variant were available.

PM6 Not assessed: no de novo event or parental testing was reported.

PP1 Not assessed: no segregation data from affected relatives were available.

PP3 Not met: SpliceAI maximum delta 0.00, below the >0.20 PP3 threshold.

PP4 Not assessed: no proband phenotype data were available to evaluate phenotype specificity.

PP5 Not met: ClinVar holds no pathogenic or likely pathogenic expert-panel assertion for this exact variant.

Benign

BA1 Not met: highest population frequency is 0.0014% (gnomAD v4.1), far below the >1% BA1 threshold.

BS1 Not met: highest observed subpopulation frequency is 0.0035%, far below the >0.3% BS1 threshold.

BS2 Not met: gnomAD v2.1 and v4.1 each report zero homozygotes, so no healthy homozygous adults are documented.

BS3 Not assessed: no validated variant-specific functional assay demonstrating preserved function was available.

BS4 Not assessed: no affected relatives tested and lacking the variant were documented.

BP2 Not assessed: no phase or family-genotype evidence showed this variant in trans or cis with a pathogenic variant.

BP5 Not assessed: no evidence of an alternate molecular diagnosis was available.

BP6 Not met: ClinVar holds no benign or likely benign expert-panel assertion for this exact variant.

BP7 Not assessed: no conservation evidence for the affected nucleotide was available, despite no predicted splice effect.

N/A · 9 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

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.

v2.1

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.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0014% · 23 / 1,613,754
0 hom · FAF 0.0013%

European (non-Finnish)

23 / 1,179,924

0.0019%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0016% · 4 / 250,716
0 hom · FAF 0.0011%

European (non-Finnish)

4 / 113,148

0.0035%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 457319)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

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.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR

20301710 ↗ Multiple Endocrine Neoplasia Type 1. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

26389271 ↗ Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health Professional Version. CLINVAR

35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

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