Final classification

Likely Pathogenic

PVS1PM2

NF2

c.863C>G

p.Ser288Ter

stop gained

Gene context NCBI Gene ↗ OncoKB ↗

NF2 encodes Merlin, a scaffolding protein that links the cell's internal skeleton to the cell membrane and helps regulate cell growth, adhesion, and signaling. Loss of its function promotes tumor formation and spread. Germline mutations in this gene cause neurofibromatosis type 2, an inherited condition marked by tumors of the nervous system and skin, along with eye abnormalities. It acts as a tumor suppressor, and the gene is also found mutated in other types of cancer.

This variant

NF2 encodes Merlin, a tumor suppressor whose loss promotes tumor formation; germline mutations cause neurofibromatosis type 2. This nonsense variant is predicted to trigger nonsense-mediated decay, eliminating Merlin and producing the loss of tumor-suppressor function that underlies NF2-related schwannomatosis.

Transcript

NM_000268.3

HGVS · transcript:coding

NM_000268.3:c.863C>G

GRCh38

chr22:29665042 C>G

GRCh37

chr22:30061031 C>G

Likely Pathogenic: PVS1 very strong (nonsense p.Ser288Ter) plus PM2 supporting (absent from gnomAD) yields Likely Pathogenic under generic ACMG/AMP 2015 (ClinGen SVI 2020, posterior 0.988), with no conflicting evidence.

Classification rationale

PVS1PM2 Likely Pathogenic

NF2 c.863C>G stop gained

PVS1 (Very Strong): Nonsense p.Ser288Ter truncates merlin at 288 of 595 amino acids and is predicted to trigger nonsense-mediated decay. PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, three large population cohorts. Together, PVS1 (very strong) plus PM2 (supporting) yields Likely Pathogenic under the ClinGen SVI 2020 combination rule (posterior probability 0.988).

PVS1 + PM2 → Likely Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000268.3 · variants mapped to exon structure

NF2 NM_000268.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met (very strong): Nonsense change p.Ser288Ter truncates merlin at 288 of 595 amino acids and is predicted to trigger nonsense-mediated decay.

pvs1_variant_assessment: consequence_class=nonsense, variant_bucket=nonsense, suggested_default_strength=PVS1, framework=PMC6185798pvs1_gene_context: lof_mechanism_supported=true, pvs1_gene_gate=eligible (germline LoF mechanism for NF2 established)VariantValidator/prefetch: p.(Ser288Ter), exon 9 (start_exon=end_exon=9), 16-exon transcript, NP_000259.1 length 595-596 aa

pvs1_generic_framework ↗PMID:25741868 ↗PMID:9643284 ↗

PM2 supporting Pathogenic

Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, three large population cohorts, in a gene with an established loss-of-function disease mechanism.

gnomad_v2gnomad_v4gnomad_canada

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 8 not met · 7 not assessed

Pathogenic

PS2 Not assessed: no de novo occurrence report or parental genotype data were available for this variant.

PS3 Not assessed: no validated functional assay specific to this variant was available to demonstrate a damaging effect.

PS4 Not met: no case-control or cohort prevalence study exists; the only observation is a single laboratory submission, short of the multiple-unrelated-patients requirement.

PM6 Not assessed: no unconfirmed de novo report or parental testing data were available for this variant.

PP1 Not assessed: no co-segregation data in affected family members were available for this variant.

PP4 Not met: no proband phenotype or family-history documentation was available to establish a highly specific phenotype.

PP5 Not met: the only ClinVar submission is a single 1-star laboratory classification, not an expert-panel classification as this criterion requires.

Benign

BA1 Not met: allele frequency is zero (absent from gnomAD v2.1, v4.1, and gnomAD-Canada), far below the 5% BA1 threshold.

BS1 Not met: allele frequency zero (absent from all three gnomAD cohorts) is far below the 0.3% BS1 threshold.

BS2 Not met: no heterozygous or homozygous observations exist in population cohorts, so no healthy-adult carrier evidence is available.

BS3 Not assessed: no functional study demonstrating preserved protein function or splicing was available for this variant.

BS4 Not assessed: no family genotype data were available to evaluate whether segregation is contradicted in affected relatives.

BP2 Not assessed: no parental or family data were available to determine whether the variant lies in cis or trans with a pathogenic variant.

BP5 Not met: no alternate genetic cause of disease was documented for this variant.

BP6 Not met: no benign or likely-benign ClinVar assertion exists for this variant, and only expert-panel classifications qualify for this criterion.

N/A · 11 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 870602)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58523216, n = 10 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

19545378 ↗ Neurofibromatosis type 2 (NF2): a clinical and molecular review.

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

9643284 ↗ Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

22825583 ↗ New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. ONCOKB

8755919 ↗ Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. ONCOKB

20301380 ↗ NF2-Related Schwannomatosis. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

32602153 ↗ Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors. CLINVAR

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