Variant classification summary

NM_000268.3:c.316G>T

NF2 · NP_000259.1:p.(Glu106Ter) · NM_000268.3

GRCh37: chr22:30035154 G>T · GRCh38: chr22:29639165 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.(Glu106Ter)

gnomAD AF

ClinVar

Likely oncogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000268.3:c.316G>T (p.Glu106Ter) is a nonsense variant in exon 3 of the NF2 gene, predicted to undergo nonsense-mediated decay and result in complete loss of merlin protein expression.

2

NF2 loss of function is an established disease mechanism for NF2-related schwannomatosis, an autosomal dominant tumor predisposition syndrome characterized by bilateral vestibular schwannomas, meningiomas, and spinal tumors.

3

This variant is absent from gnomAD v2.1 and v4.1 population databases, supporting its rarity and consistent with a pathogenic role in a rare disease.

4

The variant truncates merlin within the FERM domain (codon 106), a well-established critical functional domain required for membrane localization, cytoskeletal organization, and tumor suppressor signaling through the Hippo, mTOR, and CRL4-DCAF1 pathways.

5

Under ACMG/AMP 2015 combination rules (PMID:25741868), one very strong criterion (PVS1) plus two moderate criteria (PM1, PM2) meets the threshold for a pathogenic classification.

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	Nonsense variant NM_000268.3:c.316G>T (p.Glu106Ter) in exon 3 of 16 coding exons. Nonsense-mediated decay is expected as the premature termination codon at position 106 is >50-55 nucleotides upstream of the last exon-exon junction. NF2 loss of function is an established disease mechanism for NF2-related schwannomatosis, an autosomal dominant tumor predisposition syndrome, as demonstrated by multiple germline studies showing truncating variants as causative. No gnomAD population LoF enrichment concerns. Under ClinGen SVI PVS1 recommendations (PMC6185798), a nonsense variant in a gene with established LoF mechanism qualifies for PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:19545378 gnomad_v2 gnomad_v4
PS1	N/A	PS1 applies to missense variants where a different nucleotide change produces the same amino acid substitution as a known pathogenic variant. This is a nonsense variant and the mechanism is not applicable.
PS2	Not assessed	No de novo data available for this variant. No case reports or family studies in the reviewed literature identify de novo occurrence of c.316G>T with confirmed paternity.
PS3	Not met	No variant-specific functional data exists for NM_000268.3:c.316G>T in the reviewed literature. OncoKB annotates this variant as Likely Loss-of-function, but this is a curated inference from the variant type (nonsense), not experimental functional evidence. None of the nine reviewed publications tested this variant or a systematically characterized range that includes codon 106. Domain-level inference from FERM domain characterization supports PM1, not PS3.
PS4	Not met	No case observations of this variant in affected individuals beyond the single ClinVar submission (Variation ID 3257850). Submission details could not be extracted and no patient counts are available. The reviewed literature does not report this variant in any NF2 patient cohort.	clinvar
PS5	N/A	PS5 is not a criterion defined in the ACMG/AMP 2015 guidelines (PMID:25741868). It is used in certain somatic/VCEP frameworks but is not applicable under the generic ACMG/AMP framework.
PM1	Met	Variant truncates merlin at codon 106 within the FERM domain (N-terminal, approximately residues 20-300), a well-established critical functional domain required for merlin tumor suppressor activity. The FERM domain mediates merlin's localization to the plasma membrane and cytoskeleton, and its interaction with multiple signaling partners including the Hippo pathway, mTOR, and CRL4-DCAF1. Truncation at this position removes the entire FERM domain and all downstream functional domains (coiled-coil, C-terminal), resulting in complete loss of merlin's tumor suppressor function. The FERM domain is recognized as critical in the NF2 literature and has no reported benign population variation.	PMID:22825583 PMID:19545378
PM2	Met	Absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes) with allele frequency of 0. This is well below the 0.1% threshold for PM2 application in a gene where absent/reduced population frequency supports pathogenicity. Also absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Nonsense variant. PM5 applies when a different missense change at the same residue has been established as pathogenic. For a truncating variant, same-residue missense comparators are not relevant to the variant's mechanism. No same-residue pathogenic missense candidates were identified by automated harvesting.
PM6	Not assessed	No de novo data available. PM6 requires a de novo observation without confirmation of paternity. No publications report a de novo occurrence of c.316G>T.
PP1	Not assessed	No segregation data available. PP1 requires cosegregation with disease in multiple affected family members. No family studies or segregation data for this variant were identified in the reviewed literature.
PP2	N/A	PP2 applies to missense variants in a gene where missense variants are a common mechanism of disease and the gene has a low rate of benign missense variation. This is a nonsense (truncating) variant, not a missense change.
PP3	N/A	For a nonsense variant predicted to undergo NMD and already meeting PVS1 at very strong strength, in silico prediction tools do not provide independent evidence beyond the null effect already captured by PVS1. BayesDel score of 0.66 is consistent with a deleterious prediction but does not add independent weight. SpliceAI max delta of 0.18 indicates no significant splice impact. PP3 is not applied to nonsense variants under standard interpretation to avoid double-counting with PVS1.	spliceai bayesdel
PP4	Not assessed	No patient phenotype data provided. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No clinical information about the proband is available in the case materials.
PP5	Not met	ClinVar Variation ID 3257850 has a classification of 'Likely oncogenic' with review status 'criteria provided, single submitter' (1-star). Under the PP5 rule requiring ClinVar 3-star expert panel classification for application at supporting strength, this single-submitter somatic oncogenicity classification does not meet the threshold for PP5. The ClinVar PMIDs associated with this record (19910496, 22918138, 23619274, 34131312, 35101336) do not mention c.316G>T in their abstracts or full texts.	clinvar
BA1	Not met	Absent from gnomAD v2.1 and v4.1. Allele frequency of 0 is far below the 1% threshold for BA1. Population frequency evidence supports absence from controls rather than presence as a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	Absent from gnomAD v2.1 and v4.1. Allele frequency of 0 is far below the 0.3% threshold for BS1. Population frequency evidence supports absence from controls.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data available on homozygous observations or observations in trans with a known pathogenic variant. NF2-related schwannomatosis is an autosomal dominant disorder; homozygous or biallelic observations would not be expected in healthy adults. Not assessed due to lack of data.
BS3	Not met	No well-established functional studies demonstrate a benign effect for this variant. No experimental data exists for c.316G>T in the reviewed literature. The absence of functional studies showing a benign effect does not constitute evidence for BS3.
BS4	Not assessed	No segregation data available. BS4 requires lack of segregation in affected family members. No family studies for this variant were identified in the reviewed literature.
BP1	N/A	BP1 applies to missense variants in a gene where primarily truncating variants cause disease. This is a nonsense (truncating) variant and BP1 is not applicable.
BP2	N/A	BP2 applies to observations in trans with a pathogenic variant for a fully penetrant recessive disorder. NF2-related schwannomatosis is an autosomal dominant disorder; BP2 is not applicable.
BP4	Not met	BayesDel score of 0.66 supports a deleterious prediction, which is inconsistent with BP4 (multiple lines of computational evidence suggest no impact). SpliceAI max delta of 0.18 shows no significant splice impact, but the overall in silico evidence does not support a benign interpretation.	bayesdel spliceai
BP5	Not assessed	No data available on an alternative molecular basis for disease in a case with this variant. No case reports in the reviewed literature describe an individual harboring c.316G>T alongside a confirmed alternative molecular diagnosis.
BP6	Not met	No reputable source classifies this variant as benign or likely benign. ClinVar classifies this as 'Likely oncogenic' (somatic classification). OncoKB classifies as 'Likely Oncogenic.' No evidence supports BP6.	clinvar oncokb
BP7	N/A	BP7 applies to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence or a cryptic splice site. This is a nonsense (stop-gain) variant and BP7 is not applicable.

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