NM_001370259.2:c.300C>G

MEN1 · NP_001357188.2:p.(Ala100=) · NM_001370259.2

GRCh37: chr11:64577282 G>C · GRCh38: chr11:64809810 G>C

Gene: MEN1 Transcript: NM_001370259.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MEN1

Transcript

NM_001370259.2

Protein

NP_001357188.2:p.(Ala100=)

gnomAD AF

1.4252482100741501e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Under the generic ACMG/AMP 2015 fallback, one pathogenic supporting criterion plus one benign supporting criterion meets no benign, likely benign, likely pathogenic, or pathogenic combination and is therefore VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: synonymous substitution changes no amino acid, so no null-variant mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: synonymous change produces no altered amino acid (p.Ala100=) to compare with an established pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or other de novo evidence was available.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay showing a damaging effect was available.	PMID:25741868
PS4	Not assessed	Not assessed: no case-control or enrichment data for this exact variant were available.
PM1	N/A	Not applicable: synonymous substitution leaves the amino acid unchanged, so mutational hotspot or critical-domain membership cannot apply.	generic_acmg_combination_rules
PM2	Met	Met (supporting): extremely rare in gnomAD v4.1, 23 of 1,613,754 alleles (0.0014%), below the 0.1% threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: MEN1 disease here is autosomal dominant, and PM3 requires a recessive inheritance context.	PMID:25741868
PM4	N/A	Not applicable: synonymous substitution causes no protein length change for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue, so no pathogenic missense at the same position can be compared.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo event or parental testing was reported.
PP1	Not assessed	Not assessed: no segregation data from affected relatives were available.
PP2	N/A	Not applicable: missense constraint is irrelevant because this is a synonymous substitution with no missense change.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta 0.00, below the >0.20 PP3 threshold.	spliceai generic_acmg_combination_rules PMID:25741868
PP4	Not assessed	Not assessed: no proband phenotype data were available to evaluate phenotype specificity.
PP5	Not met	Not met: ClinVar holds no pathogenic or likely pathogenic expert-panel assertion for this exact variant.	clinvar
BA1	Not met	Not met: highest population frequency is 0.0014% (gnomAD v4.1), far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: highest observed subpopulation frequency is 0.0035%, far below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report zero homozygotes, so no healthy homozygous adults are documented.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated variant-specific functional assay demonstrating preserved function was available.	PMID:25741868
BS4	Not assessed	Not assessed: no affected relatives tested and lacking the variant were documented.
BP1	N/A	Not applicable: the gene's truncating-variant mechanism is irrelevant because no missense change is present (synonymous, p.Ala100=).	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase or family-genotype evidence showed this variant in trans or cis with a pathogenic variant.	PMID:25741868
BP3	N/A	Not applicable: synonymous substitution causes no protein length change within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI maximum delta 0.00, below the <0.10 BP4 threshold.	spliceai generic_acmg_combination_rules PMID:25741868
BP5	Not assessed	Not assessed: no evidence of an alternate molecular diagnosis was available.
BP6	Not met	Not met: ClinVar holds no benign or likely benign expert-panel assertion for this exact variant.	clinvar
BP7	Not assessed	Not assessed: no conservation evidence for the affected nucleotide was available, despite no predicted splice effect.	spliceai PMID:25741868

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.