NM_000268.3:c.1035G>A (p.Met345Ile) is a missense variant in the NF2 gene, which encodes merlin, a tumor suppressor associated with NF2-related schwannomatosis. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, satisfying PM2 at the supporting level.1 The variant is a missense change in NF2, a gene where the primary pathogenic mechanism is loss of function through truncating variants. This satisfies BP1 at the supporting level.2 Multiple in silico predictors (REVEL 0.26, BayesDel -0.23067, SpliceAI 0.00) concordantly predict a benign or non-damaging effect, satisfying BP4 at the supporting level.3 No functional data, case observations, segregation data, or de novo reports were identified for this variant. No ClinVar entry with an expert panel classification exists for this variant.4 With 2 supporting benign criteria (BP1, BP4) and 1 supporting pathogenic criterion (PM2), the variant is classified as Likely Benign per the generic ACMG/AMP 2015 classification framework (2 supporting benign criteria = Likely Benign).5
NF2
Final classification
Likely Benign
NF2 c.1035G>A · p.Met345Ile
NF2
NM_000268.3:c.1035G>A (p.Met345Ile) is a missense variant in the NF2 gene, which encodes merlin, a tumor suppressor associated with NF2-related schwannomatosis.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP1 supporting, BP4 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP1BP4
Likely Benign
NF2 c.1035G>A
PM2 + BP1 + BP4
→
Likely Benign
Gene diagram
· NM_000268.3 · variants mapped to exon structure
NF2
NM_000268.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 19 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000268.3:c.1035G>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not present in large population cohorts. Under generic ACMG/AMP, absence from population databases supports a pathogenic interpretation at the supporting level.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0.
✓
BP1
supporting
Benign
NM_000268.3:c.1035G>A is a missense variant in NF2, a gene where the primary pathogenic mechanism is loss of function through truncating variants. The gene-level PVS1 assessment confirmed that NF2-related schwannomatosis is caused by loss-of-function variants, with pathogenic variants often being truncating. A missense variant in a gene where truncating variants are the established disease mechanism satisfies BP1 at the supporting level.
NF2 disease mechanism is primarily loss-of-function via truncating variants.Literature review confirms germline pathogenic variants in NF2 are often truncating.
✓
BP4
supporting
Benign
Multiple in silico tools predict a benign or non-damaging effect for NM_000268.3:c.1035G>A (p.Met345Ile). REVEL score is 0.26 (below the pathogenic threshold of 0.5). BayesDel score is -0.23067 (negative, consistent with a benign prediction). SpliceAI max delta score is 0.00, predicting no impact on splicing. The concordance of multiple computational predictors supports a benign interpretation at the supporting level.
REVEL: 0.26 (benign range).BayesDel: -0.23067 (benign prediction).SpliceAI: max delta 0.00 (no splice impact).
Assessed · not applied
Pathogenic
PS2
No de novo observation has been reported for NM_000268.3:c.1035G>A.
PS3
No variant-specific functional data has been identified for NM_000268.3:c.1035G>A (p.Met345Ile).
PS4
No case-control or case observation data have been reported for NM_000268.3:c.1035G>A.
PM1
Residue 345 (Met345) is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no domain-level functional characterization specific to this residue was identified in the available evidence.
PM5
No same-residue pathogenic missense comparator variants were identified at codon 345 of NF2.
PM6
No de novo observation of NM_000268.3:c.1035G>A with confirmed parentage has been reported.
PP1
No segregation data are available for NM_000268.3:c.1035G>A.
PP2
NF2 is a tumor suppressor gene where the primary pathogenic mechanism is loss of function through truncating variants, not missense variation.
PP3
Multiple in silico tools predict a benign or non-damaging effect.
PP4
No phenotypic or family history data are available for the individual carrying NM_000268.3:c.1035G>A.
PP5
The ClinVar record retrieved by the pipeline is for a different variant (NM_000268.4:c.1266G>A, p.Glu422=), not NM_000268.3:c.1035G>A.
Benign
BA1
NM_000268.3:c.1035G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_000268.3:c.1035G>A is absent from gnomAD.
BS2
No data are available on observation of NM_000268.3:c.1035G>A in healthy adult individuals.
BS3
No functional studies demonstrating a benign effect of NM_000268.3:c.1035G>A (p.Met345Ile) have been identified.
BS4
No segregation data demonstrating lack of co-segregation with disease are available for NM_000268.3:c.1035G>A.
BP2
No data are available on whether NM_000268.3:c.1035G>A has been observed in trans with a known pathogenic NF2 variant.
BP5
No case with an alternate molecular basis for disease has been reported for an individual carrying NM_000268.3:c.1035G>A.
BP6
The ClinVar record retrieved by the pipeline is for a different variant (NM_000268.4:c.1266G>A, p.Glu422=), not NM_000268.3:c.1035G>A.
N/A · 3
PVS1 · PS1 · BP7
Research & evidence
Population frequency · supports benign
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.26. BayesDel score = -0.23067.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NF2, a scaffolding protein, is frequently altered in mesothelioma, meningioma and nerve sheath tumors.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR