NM_000268.3:c.1035G>A

NF2 · NP_000259.1:p.(Met345Ile) · NM_000268.3

GRCh37: chr22:30067850 G>A · GRCh38: chr22:29671861 G>A

Gene: NF2 Transcript: NM_000268.3

Final call

Likely Benign

PM2 supporting BP1 supporting BP4 supporting

Variant details

Gene

NF2

Transcript

NM_000268.3

Protein

NP_000259.1:p.(Met345Ile)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	N/A	NM_000268.3:c.1035G>A is a missense variant (p.Met345Ile) and does not fall into the PVS1 null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) is not applicable to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No known pathogenic variant with the same amino acid change (p.Met345Ile) has been identified. No comparator data available.
PS2	Not met	No de novo observation has been reported for NM_000268.3:c.1035G>A. No case-level data with confirmed parentage is available.
PS3	Not met	No variant-specific functional data has been identified for NM_000268.3:c.1035G>A (p.Met345Ile). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No published functional studies of this variant or a systematically characterized range spanning residue 345 were found.	oncokb
PS4	Not met	No case-control or case observation data have been reported for NM_000268.3:c.1035G>A. The ClinVar record matched by the pipeline is for a different variant (NM_000268.4:c.1266G>A, p.Glu422=) and is not usable for this assessment. The only publication linked (PMID:25394175) is a general cancer genetics referral guideline that does not mention NF2 or this variant.	clinvar PMID:25394175
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework; it is not part of the generic ACMG classification scheme.
PM1	Not met	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. The variant lies in the alpha-helical domain of merlin, but domain membership alone without residue-specific functional characterization or hotspot significance does not satisfy PM1.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue pathogenic missense comparator variants were identified at codon 345 of NF2. The PM5 candidate search yielded zero candidates at this position. The ClinVar candidate matched by the pipeline (NM_000268.4:c.1266G>A, p.Glu422=) is at a different codon and is not usable for PM5.	pm5_candidates
PM6	Not met	No de novo observation of NM_000268.3:c.1035G>A with confirmed parentage has been reported.
PP1	Not met	No segregation data are available for NM_000268.3:c.1035G>A. No family studies or co-segregation analyses have been reported.
PP2	Not met	NF2 is a tumor suppressor gene where the primary pathogenic mechanism is loss of function through truncating variants, not missense variation. No missense constraint metric (e.g., Z-score) is available to support a low rate of benign missense variation. PP2 requires both a low rate of benign missense variation and missense variants as a common disease mechanism, neither of which is established here.	pvs1_gene_context
PP3	Not met	Multiple in silico tools predict a benign or non-damaging effect. REVEL score is 0.26 (below the 0.5 threshold for pathogenicity prediction). BayesDel score is -0.23067 (negative, indicating a benign prediction). SpliceAI max delta score is 0.00, predicting no splice impact. No computational tool supports a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No phenotypic or family history data are available for the individual carrying NM_000268.3:c.1035G>A. PP4 requires the patient's phenotype or family history to be highly specific for NF2-related schwannomatosis.
PP5	Not met	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. The ClinVar entry is not an exact match and cannot be used for PP5. Even if it were the same variant, the review status is 'criteria provided, single submitter' — not the 3-star expert panel required for PP5 application at supporting level.	clinvar
BA1	Not met	NM_000268.3:c.1035G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_000268.3:c.1035G>A is absent from gnomAD. The allele frequency of 0% is below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on observation of NM_000268.3:c.1035G>A in healthy adult individuals. The variant is absent from population databases, precluding BS2 assessment.
BS3	Not met	No functional studies demonstrating a benign effect of NM_000268.3:c.1035G>A (p.Met345Ile) have been identified. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not met	No segregation data demonstrating lack of co-segregation with disease are available for NM_000268.3:c.1035G>A.
BP1	Met	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.	pvs1_gene_context
BP2	Not met	No data are available on whether NM_000268.3:c.1035G>A has been observed in trans with a known pathogenic NF2 variant.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No case with an alternate molecular basis for disease has been reported for an individual carrying NM_000268.3:c.1035G>A.
BP6	Not met	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. The ClinVar entry is not an exact match and cannot be used for BP6. Even if it were the same variant, the review status is 'criteria provided, single submitter' — not the 3-star expert panel required for BP6 application.	clinvar
BP7	N/A	NM_000268.3:c.1035G>A is a missense variant, not a synonymous/silent variant. BP7 applies only to synonymous variants predicted not to affect splicing, which is not the case here.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.