Variant classification summary

NM_000268.3:c.604G>T

NF2 · NP_000259.1:p.(Glu202Ter) · NM_000268.3

GRCh37: chr22:30054182 G>T · GRCh38: chr22:29658193 G>T

Gene: NF2 Transcript: NM_000268.3

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 moderate

Variant details

Gene

NF2

Transcript

NM_000268.3

Protein

NP_000259.1:p.(Glu202Ter)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000268.3:c.604G>T (p.Glu202Ter) is a nonsense variant in exon 7 of NF2, creating a premature termination codon predicted to trigger nonsense-mediated decay or produce a severely truncated merlin protein lacking the FERM domain F3 lobe and all downstream domains.

2

NF2 is a well-established tumor suppressor gene where germline loss-of-function variants cause NF2-related schwannomatosis, an autosomal dominant tumor predisposition syndrome characterized by bilateral vestibular schwannomas, meningiomas, and other nervous system tumors.

3

Truncating NF2 mutations, including nonsense variants, are associated with a more severe disease phenotype with earlier age of onset compared to missense or splice site mutations, as demonstrated in the largest genotype-phenotype study of 125 NF2 families.

4

The variant is absent from gnomAD v2.1 (~141,456 individuals) and gnomAD v4.1 (~807,162 individuals), consistent with a rare disease-causing variant not tolerated in the general population.

5

The premature stop at codon 202 occurs within the FERM domain, a critical functional domain required for merlin membrane association and tumor suppressor activity; the truncation removes the F3 subdomain and all C-terminal domains essential for merlin-mediated growth regulation.

6

Combined evidence satisfies ACMG/AMP Pathogenic classification: PVS1 (Very Strong) + PM2 (Moderate) + PM1 (Moderate).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	Met	NM_000268.3:c.604G>T is a nonsense variant (p.Glu202Ter) in exon 7 of 16 coding exons in NF2, a tumor suppressor gene where loss-of-function is an established germline disease mechanism for NF2-related schwannomatosis. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with confirmed LoF disease mechanism are assigned PVS1 at very strong strength. NMD is predicted as the premature termination codon (position 202 of 596) occurs more than 50 nucleotides upstream of the last exon junction.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies when the same amino acid change has been established as pathogenic; this is a nonsense (stop-gain) variant, not a missense change amenable to PS1 evaluation.
PS2	Not assessed	No de novo data is available in the case materials for this variant.
PS3	Not met	No variant-specific functional studies were identified for p.Glu202Ter or for a systematically characterized range that includes codon 202. OncoKB's 'Likely Loss-of-function' label is a bioinformatic prediction, not experimental functional data. No publication tested this variant or a saturated range encompassing it in a functional assay.
PS4	Not met	The variant is absent from gnomAD population databases, but no clinical cohort or case series reporting this specific variant in affected individuals was identified. COSMIC reports n=2 somatic occurrences, but germline prevalence data in NF2-affected cohorts is unavailable.
PS5	N/A	PS5 is not a standard ACMG/AMP criterion; likely intended for PS5 alternative applications. This variant does not fit any recognized PS5 use case.
PM1	Met	The nonsense variant p.Glu202Ter truncates merlin within the FERM domain (residues ~1-300), a well-characterized functional domain essential for membrane association and tumor suppressor activity. The premature stop at codon 202 removes the F3 lobe of the FERM domain and all downstream domains, including the alpha-helical and C-terminal regions. The FERM domain is established as critical for merlin function through extensive literature on NF2 pathogenesis.	PMID:19545378 PMID:22825583 PMID:9643284
PM2	Met	NM_000268.3:c.604G>T is absent from gnomAD v2.1 (~141,456 individuals), gnomAD v4.1 (~807,162 individuals), and gnomAD-Canada v1.0. Under generic ACMG, PM2 applies for variants with population frequency <0.1% that are absent from large population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies when a different missense change at the same residue has been classified as pathogenic. This variant is a nonsense (stop-gain) change producing p.Glu202Ter; PM5 is not applicable to nonsense variants because the pathogenic mechanism (protein truncation via NMD) differs fundamentally from missense alterations. Additionally, no ClinVar comparator variants at codon 202 were identified with pathogenic classification.
PM6	Not assessed	No de novo data is available for this variant in the case materials.
PP1	Not assessed	No family segregation data is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense (stop-gain) variant, not a missense change.
PP3	N/A	PP3 evaluates in silico predictions of deleterious effect for missense variants. This is a nonsense variant; protein-truncating effect is self-evident from the variant type and in silico pathogenicity prediction does not add independent evidence. Per PMC6185798, PP3 should not be stacked with PVS1 for variants where the deleterious mechanism is already captured by the variant type.
PP4	Not assessed	No patient phenotype data is available in the case materials to assess whether the clinical presentation is specific for NF2-related schwannomatosis.
PP5	Not met	ClinVar VariationID 3231107 is associated with NM_000268.4:c.718G>T (p.Gly240Trp), NOT NM_000268.3:c.604G>T (p.Glu202Ter). The ClinVar match is not an exact match for this variant. The classification is 'Uncertain significance, criteria provided, single submitter' from Ambry Genetics — even if it were the correct variant, it is not from an expert panel and does not meet the 3-star EP threshold. PP5 is not met.
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1. BA1 requires allele frequency >1% in population databases, which is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1. BS1 requires allele frequency >0.3% in population databases, which is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data available on observation of this variant in healthy adults. BS2 requires observation in a healthy adult with full penetrance expected at an early age.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect were identified for p.Glu202Ter. OncoKB suggests Likely Loss-of-function, consistent with a deleterious rather than benign effect. No publication reports experimental data showing normal protein function for this variant.
BS4	Not assessed	No cosegregation data is available. BS4 requires lack of segregation in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is itself a truncating (nonsense) variant, not a missense change.
BP2	Not assessed	No data on in trans observation with a known pathogenic variant is available.
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion in a repetitive region.
BP4	N/A	BP4 evaluates in silico predictions suggesting no impact for missense or splice variants. This is a nonsense variant where the protein-truncating effect is self-evident; in silico tools are not designed to assess stop-gain variants. SpliceAI max delta score of 0.14 indicates no cryptic splice effect, but BP4 does not apply to nonsense variants.
BP5	Not assessed	No data available on this variant being observed in a case with an alternate molecular basis for disease.
BP6	Not met	ClinVar VariationID 3231107 is associated with NM_000268.4:c.718G>T (p.Gly240Trp), NOT this variant. No reputable source reports this specific variant as benign or likely benign. Even the matched ClinVar record is classified as Uncertain significance, which does not support BP6.
BP7	N/A	This is a nonsense variant. BP7 applies to synonymous variants with no predicted splice impact.

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