Variant classification summary

NM_000244.3:c.435C>T

MEN1 · NP_000235.2:p.(Ser145=) · NM_000244.3

GRCh37: chr11:64577147 G>A · GRCh38: chr11:64809675 G>A

Gene: MEN1 Transcript: NM_000244.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 supporting benign BP2 supporting benign BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

MEN1

Transcript

NM_000244.3

Protein

NP_000235.2:p.(Ser145=)

gnomAD AF

0.035370739123915924 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000244.3:c.435C>T is a synonymous variant (p.Ser145=) in exon 2 of the MEN1 gene.

2

This variant is present at a high allele frequency in population databases: 2.84% overall in gnomAD v2.1 (8021/282758 alleles, 189 homozygotes) and 3.54% in gnomAD v4.1 (57090/1614046 alleles, 1240 homozygotes), with a maximum subpopulation frequency of 6.39% in the European (Finnish) population. This far exceeds the BA1 threshold of >1%, satisfying stand-alone benign evidence.

3

The variant has been observed in a homozygous state in 189 individuals in gnomAD v2.1 and 1240 individuals in gnomAD v4.1. For a highly penetrant autosomal dominant disorder such as MEN1, the observation of multiple healthy adult homozygotes is incompatible with pathogenicity.

4

SpliceAI predicts no splice impact (max delta score = 0.00), consistent with a silent synonymous change that does not alter normal splicing.

5

ClinVar classifies this variant as Benign, with consensus across 18 clinical laboratories (ClinVar ID 96252).

6

No pathogenic evidence was identified: no de novo occurrences, no functional studies demonstrating damage, no case-control enrichment, no cosegregation data, and no in silico predictions of pathogenicity.

7

Under generic ACMG/AMP 2015 rules, BA1 (stand-alone benign) alone is sufficient for a Benign classification. The additional supporting benign criteria (BS2, BP2, BP4, BP6, BP7) further reinforce the benign interpretation.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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	PVS1 is not applicable: NM_000244.3:c.435C>T is a synonymous variant (p.Ser145=) that does not fall into any default null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) confirms this variant is not eligible for generic PVS1 scoring.	pvs1_generic_framework
PS1	Not met	PS1 is not met: no known pathogenic variant has been established with the same protein consequence (p.Ser145=) at codon 145. This is a synonymous variant, and no other synonymous change at c.435 has been reported as pathogenic.
PS2	Not met	PS2 is not met: no de novo occurrence (maternity and paternity confirmed) has been reported for NM_000244.3:c.435C>T in any database or literature source.
PS3	Not met	PS3 is not met: no well-established functional studies have been performed on this specific variant that demonstrate a damaging effect. No functional assays were identified in literature or curated databases.
PS4	Not met	PS4 is not met: no case-control study demonstrates enrichment of this variant in affected individuals versus controls. The high population frequency (gnomAD AF 2.84–3.54%) is inconsistent with pathogenicity and would contradict any PS4 assertion.	gnomad_v2 gnomad_v4
PS5	Not met	PS5 is not met: no evidence that this variant has been detected in trans with a pathogenic variant for a recessive disorder.
PM1	Not met	PM1 is not met: codon 145 is not located in a statistically significant mutational hotspot or a well-established critical functional domain of menin. The Cancer Hotspots analysis confirms this residue is not significant.
PM2	Not met	PM2 is not met: the variant is common in population databases. gnomAD v2.1 reports an allele frequency of 2.84% (8021/282758 alleles) and v4.1 reports 3.54% (57090/1614046 alleles), both far exceeding the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 is not applicable: this is a synonymous variant (p.Ser145=) with no missense change at the same residue. The pm5_candidates module confirmed no same-residue missense comparators could be identified.
PM6	Not met	PM6 is not met: no assumed de novo occurrence (parental status unconfirmed) has been reported for this variant in any available source.
PP1	Not met	PP1 is not met: no cosegregation data with disease has been reported for this variant in affected families.
PP2	N/A	PP2 is not applicable: this criterion applies to missense variants in genes with a low rate of benign missense variation. NM_000244.3:c.435C>T is a synonymous variant, not a missense change.
PP3	Not met	PP3 is not met: no in silico tools predict a damaging effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel scores are not available for this variant, and no HCI prior probability is assigned to MEN1.	spliceai
PP4	Not met	PP4 is not met: no patient-specific phenotype or family history data are available to assess specificity for MEN1-related disease.
PP5	Not met	PP5 is not met: no reputable source has reported this variant as pathogenic. ClinVar classifies it as Benign (18 clinical laboratories; ClinVar ID 96252).	clinvar
BA1	Met	BA1 is met: NM_000244.3:c.435C>T is present at a high allele frequency in population databases, far exceeding the 1% threshold. In gnomAD v2.1, the overall allele frequency is 2.84% (8021/282758 alleles, 189 homozygotes), with the highest subpopulation frequency of 6.39% in European (Finnish) (1606/25120 alleles, 63 homozygotes). In gnomAD v4.1, the overall frequency is 3.54% (57090/1614046 alleles, 1240 homozygotes), with 6.38% in Finnish (4082/64030 alleles, 142 homozygotes). This allele frequency is incompatible with a highly penetrant autosomal dominant disorder such as MEN1.	gnomad_v2 gnomad_v4
BS1	Met	BS1 is met: the allele frequency of 2.84–3.54% exceeds the >0.3% threshold. However, BA1 (stand-alone benign) is also met and subsumes BS1; BS1 is noted here for completeness but is superseded by the stronger BA1 criterion.	gnomad_v2 gnomad_v4
BS2	Met	BS2 is met: the variant has been observed in 189 homozygous individuals in gnomAD v2.1 and 1240 homozygotes in gnomAD v4.1, as well as thousands of heterozygotes. gnomAD excludes individuals with severe pediatric disease; for a dominant high-penetrance cancer syndrome such as MEN1, the observation of healthy adults harboring this variant in the homozygous and heterozygous state supports a benign interpretation.	gnomad_v2 gnomad_v4
BS3	Not met	BS3 is not met: no well-established functional studies specifically evaluating NM_000244.3:c.435C>T have been published. While in silico tools predict no splice impact, this constitutes computational rather than functional evidence.
BS4	Not met	BS4 is not met: no family studies demonstrating lack of cosegregation with MEN1-related disease have been reported for this variant.
BP1	N/A	BP1 is not applicable: this criterion applies to missense variants in genes where primarily truncating variants cause disease. NM_000244.3:c.435C>T is a synonymous variant, not a missense change.
BP2	Met	BP2 is met: given the high population frequency of this variant (AF 2.84–3.54%), it is statistically certain to occur in trans with known pathogenic MEN1 variants in healthy individuals. MEN1 is a fully penetrant autosomal dominant disorder; the absence of disease in individuals carrying both this variant and a pathogenic MEN1 variant supports a benign classification.	gnomad_v2 gnomad_v4
BP4	Met	BP4 is met: SpliceAI predicts no splice impact (max delta score = 0.00). For a synonymous variant, the absence of a predicted splicing alteration constitutes computational evidence of no functional impact. Note that BP7 is the more specific criterion for synonymous variants; BP4 is applied here as additional corroborating computational evidence.	spliceai
BP5	Not met	BP5 is not met: no evidence that this variant has been observed in a case where an alternate molecular basis for disease was identified.
BP6	Met	BP6 is met: ClinVar reports NM_000244.3:c.435C>T as Benign, supported by 18 clinical laboratories (ClinVar ID 96252). The inter-laboratory consensus across 18 submitters provides reputable source evidence for a benign classification.	clinvar
BP7	Met	BP7 is met: NM_000244.3:c.435C>T is a synonymous variant (p.Ser145=). SpliceAI predicts no significant splice impact (max delta score = 0.00), indicating that this variant does not create a novel splice site or disrupt the splice consensus sequence. The nucleotide is not predicted to affect normal splicing.	spliceai

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