NF2

Final classification

Likely Pathogenic

NF2 c.863C>G · p.Ser288Ter

NF2

PVS1 (Very Strong): Nonsense p.Ser288Ter truncates merlin at 288 of 595 amino acids and is predicted to trigger nonsense-mediated decay.

Gene

NF2

Transcript

NM_000268.3

HGVS · transcript:coding

NM_000268.3:c.863C>G

Consequence

N/A

GRCh38

chr22:29665042 C>G

GRCh37

chr22:30061031 C>G

Basis 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. ▾

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

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

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

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

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