About NF2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF2 c.1035G>A, p.(Met345Ile)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 2
BP1Supporting
BP1 · supporting
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.
BP4Supporting
BP4 · supporting
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.
Recorded classification: Likely benign
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 19 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 3
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0.
Sources
BP1 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- NF2 disease mechanism is primarily loss-of-function via truncating variants.
- Literature review confirms germline pathogenic variants in NF2 are often truncating.
Sources
pvs1_gene_context
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign range).
- BayesDel: -0.23067 (benign prediction).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
Not met · 19 · evaluated, threshold not reached
PS2 No de novo observation has been reported for NM_000268.3:c.1035G>A. No case-level data with confirmed parentage is available. Details ▾Hide ▴
Still missing
- No de novo data available for this variant.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
Still missing
- No functional studies available for this variant or a systematically characterized range including residue 345.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- ClinVar best candidate is an inexact match for a different variant
- no case observations available.
Still missing
- No case observations or case-control studies for this variant.
Sources
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. 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. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not in a statistically significant hotspot.
Still missing
- No residue-specific functional domain characterization for position 345.
PM5 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. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variants at residue 345 found in ClinVar or candidate databases.
Sources
pm5_candidates
PM6 No de novo observation of NM_000268.3:c.1035G>A with confirmed parentage has been reported. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No segregation data are available for NM_000268.3:c.1035G>A. No family studies or co-segregation analyses have been reported. Details ▾Hide ▴
Still missing
- No segregation or family studies available.
PP2 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. Details ▾Hide ▴
Evidence considered
- NF2 disease mechanism is primarily loss-of-function via truncating variants
- missense constraint data not available.
Still missing
- No missense constraint metric available for NF2.
Sources
pvs1_gene_context
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign range).
- BayesDel: -0.23067 (benign prediction).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
PP4 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. Details ▾Hide ▴
Still missing
- No clinical phenotype or family history provided.
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. 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. Details ▾Hide ▴
Evidence considered
- ClinVar best candidate (variation ID 1764288) is NM_000268.4:c.1266G>A
- not c.1035G>A
- exact_match=false.
- Single submitter (Ambry Genetics)
- not 3-star expert panel.
Sources
BA1 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%. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- allele frequency = 0%.
Sources
BS1 NM_000268.3:c.1035G>A is absent from gnomAD. The allele frequency of 0% is below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- allele frequency = 0%.
Sources
BS2 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. Details ▾Hide ▴
Still missing
- No data on observation in healthy controls.
BS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no benign functional data.
Still missing
- No functional studies available.
Sources
BS4 No segregation data demonstrating lack of co-segregation with disease are available for NM_000268.3:c.1035G>A. Details ▾Hide ▴
Still missing
- No segregation data available.
BP2 No data are available on whether NM_000268.3:c.1035G>A has been observed in trans with a known pathogenic NF2 variant. Details ▾Hide ▴
Still missing
- No data on variant in trans.
BP5 No case with an alternate molecular basis for disease has been reported for an individual carrying NM_000268.3:c.1035G>A. Details ▾Hide ▴
Still missing
- No data on alternate molecular diagnosis in a carrier.
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. 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. Details ▾Hide ▴
Evidence considered
- ClinVar best candidate is an inexact match for a different variant.
- Single submitter
- not 3-star expert panel.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant type eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo known pathogenic variant with the same amino acid change (p.Met345Ile) has been identified. No comparator data available. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_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. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework; it is not part of the generic ACMG classification scheme. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NF2
- Transcript
- NM_000268.3
- Coding (HGVS c.)
- NM_000268.3:c.1035G>A
- Protein (HGVS p.)
- NP_000259.1:p.(Met345Ile)
- GRCh38
- chr22:29671861 G>A
- GRCh37
- chr22:30067850 G>A
- ClinVar
- 1764288
Gene diagram
Every interpreted variant in NF2, mapped onto the exon structure of NM_000268.3. Select a row to find it on the plot.
NF2NM_000268.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NF2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.260
- BayesDel
- -0.231
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign range).
- BayesDel: -0.23067 (benign prediction).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign range).
- BayesDel: -0.23067 (benign prediction).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
BP7 N/ANM_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. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.26. BayesDel score = -0.23067.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 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.Hampel H et al. · 2015This is a practice guideline from ACMG and NSGC providing referral indications for cancer predisposition assessment. It discusses hereditary cancer syndromes including NF1 but does not mention NF2 or NF2-related schwannomatosis. NM_000268.3:c.1035G>A was not identified in this publication.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000268.3%3Ac.1035G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-30067850-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-29671861-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/22-29671861-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000268.3%3Ac.1035…
- OncoKB ↗www.oncokb.org/gene/NF2/M345I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NF2+c.1035G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
Error retrieving ClinVar entry.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.