NM_000244.3:c.1311G>A

MEN1 · NP_000235.2:p.(Leu437=) · NM_000244.3

GRCh37: chr11:64572560 C>T · GRCh38: chr11:64805088 C>T

Gene: MEN1 Transcript: NM_000244.3

Final call

Likely Benign

BS1 strong benign BP7 supporting benign

Variant details

Gene

MEN1

Transcript

NM_000244.3

Protein

NP_000235.2:p.(Leu437=)

gnomAD AF

0.0014502899340833623 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	This 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is not applicable because this variant does not produce an amino acid substitution.
PS2	Not assessed	No confirmed de novo occurrence with parental testing was identified.
PS3	Not assessed	No well-established functional study showing a damaging effect of this exact variant was identified.
PS4	Not met	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.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	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.	hotspots
PM2	Not met	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%.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 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.
PM4	N/A	PM4 is not applicable because this variant does not change protein length.
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not assessed	No apparent de novo occurrence without confirmed parentage was identified.
PP1	Not assessed	No segregation data were identified for this exact variant.
PP2	N/A	PP2 is not applicable because this variant is not a missense change.
PP3	Not met	Available computational evidence does not support a damaging splicing effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.08.	spliceai
PP4	Not assessed	No case-specific phenotype information was provided to determine whether the clinical presentation is highly specific for MEN1 caused by this variant.
PP5	N/A	PP5 was not applied because a pathogenic assertion from an external source without independently reviewable evidence was not used for this interpretation.
BA1	Not met	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%.	gnomad_v4
BS1	Met	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 gnomad_v4
BS2	Not assessed	Population observations alone were not considered sufficient to establish this criterion for a dominant, age-related tumor predisposition condition.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing a benign effect of this exact variant was identified.
BS4	Not assessed	No nonsegregation data were identified for this exact variant.
BP1	N/A	BP1 is not applicable because this variant is not a missense change.
BP2	Not assessed	No phase data or co-occurrence data were identified.
BP3	Not assessed	No evidence was identified that this variant lies in a repetitive region without a known function.
BP4	N/A	BP4 was not separately applied because this is a synonymous variant and BP7 is the more specific benign computational criterion for this context.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular cause explaining the phenotype.
BP6	N/A	BP6 was not applied because benign assertions from external databases were not used as a standalone criterion without independent evidence review.
BP7	Met	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.	spliceai

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.