NF1 c.2092_2093insT, p.(Pro698LeufsTer2)

Reasoning

NF1 loss of function is an established germline disease mechanism, and the applicable NF1 CSPEC ruleset contains no usable PVS1-specific rule payload, so the ClinGen SVI generic PVS1 framework applies. NM_001042492.2:c.2092_2093insT is a coding frameshift producing NP_001035957.1:p.(Pro698LeufsTer2), truncating the 2,840-amino-acid protein after predicted residue 699. Variant Validator places it in exon 18, whose coding interval is c.2025-c.2104, and shows many downstream coding exons through c.8520; therefore the premature termination is not in the last exon or within the terminal-exon region where NMD escape is a concern. The transcript is a RefSeq-selected NF1 transcript with a validated coding and protein consequence, and the affected exon is not a distal non-critical exon. No named SVI or VCEP downgrade rule is triggered: this is a frameshift, not a canonical splice-site variant; the predicted truncation is expected to undergo NMD; and no evidence indicates that exon 18 is biologically irrelevant or enriched for tolerated loss-of-function variation. Apply full generic PVS1 weight as very strong.

Rule

ClinGen SVI generic PVS1 framework (PMC6185798); full-strength PVS1 for a truncating frameshift with established NF1 loss-of-function mechanism and no applicable downgrade.

Evidence considered

• The NF1 ClinGen CSPEC ruleset identifies NM_000267.3 as its preferred transcript but provides no criteria or PVS1-specific rule payload; therefore no gene-specific PVS1 downgrade rule is available.
• The ClinGen SVI PVS1 framework supports full-strength PVS1 for a loss-of-function frameshift when loss of function is an established disease mechanism, absent an NMD, transcript-relevance, critical-exon, or distal-region downgrade.
• NM_001042492.2:c.2092_2093insT is validated as a coding frameshift yielding NP_001035957.1:p.(Pro698LeufsTer2), with the predicted protein ending at residue 699 rather than the 2,840-residue reference length.
• Variant Validator places the change in exon 18 (coding interval c.2025-c.2104) and shows numerous downstream coding exons through c.8520, supporting NMD rather than escape from a terminal exon.
• The variant is on a RefSeq-selected transcript with a defined NF1 transcript description and validated protein consequence; no evidence in the case data indicates that the affected exon is non-critical or enriched for tolerated loss-of-function variation.

Sources

Reasoning

The governing NF1 ClinGen specification is present but contains no usable PM2 population rule or alternate threshold, so the supplied generic ClinGen-SVI recommendation applies. The variant is absent from the all-comers gnomAD v2.1 and v4.1 datasets; the available non-cancer subset queries also record absence. Thus the observed allele frequency is 0, meeting the generic PM2 supporting threshold of <=0.0001. No ancestry-specific frequency or cohort artifact contradicts this result.

Rule

{'source': 'generic ClinGen-SVI recommendation', 'threshold': 'allele frequency <= 0.0001', 'threshold_publication': 'ClinGen SVI recommendation, PMID:25741868', 'strength': 'supporting'}

Evidence considered

• The NF1 ClinGen specification is the governing framework, but its retrieved ruleset provides no alternate PM2 threshold or population-source restriction.
• gnomAD v2.1 reports the variant as absent in the all-comers dataset.
• gnomAD v4.1 reports the variant as absent in the all-comers dataset.
• The case evidence separately records the variant as absent from the queried gnomAD v2.1 non-cancer and v3.1 non-cancer subsets.
• The supplied generic PM2 threshold is allele frequency <=0.0001 at supporting strength, based on the ClinGen SVI recommendation cited as PMID:25741868.

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion. The ClinVar query found no exact record for NM_001042492.2:c.2092_2093insT, with no variation ID, classification, review status, or expert-panel assertion. OncoKB and general literature classifications do not satisfy this rule. PP5 is therefore not met.

Rule

Apply only when the exact variant has a ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• ClinVar returned no exact match for NM_001042492.2:c.2092_2093insT; variation IDs, classification, review status, and submissions are absent.
• No expert-panel Pathogenic or Likely pathogenic ClinVar assertion is available to support PP5.
• The available OncoKB label and non-expert or gene-level literature are excluded from PP5 under the specified rule.

Sources

Reasoning

The governing NF1 ClinGen specification is present but contains no usable population-frequency rule or threshold for BA1, so the generic ACMG/AMP threshold applies. The variant is absent from the all-comers gnomAD v2.1 and v4.1 datasets, and the evidence also records absence in the available non-cancer subset queries. Therefore its observed allele frequency is 0, which is below the generic BA1 stand-alone threshold of 0.05; BA1 is not met. This conclusion does not treat absence as a stand-alone benign finding.

Rule

{'source': 'generic ACMG/AMP', 'threshold': 'allele frequency >= 0.05', 'threshold_publication': 'ACMG/AMP 2015, PMID:25741868', 'interpretation': 'Observed absence cannot meet BA1.'}

Evidence considered

• The NF1 ClinGen specification is the governing framework, but its retrieved ruleset provides no population-specific BA1 threshold.
• gnomAD v2.1 reports the variant as absent in the all-comers dataset.
• gnomAD v4.1 reports the variant as absent in the all-comers dataset.
• The case evidence separately records the variant as absent from the queried gnomAD v2.1 non-cancer and v3.1 non-cancer subsets.
• Under the generic ACMG/AMP 2015 threshold, BA1 requires allele frequency >=0.05; this published threshold is from ACMG/AMP 2015 (PMID:25741868).

Sources

Reasoning

The governing NF1 ClinGen specification is present but contains no usable BS1 population-frequency rule or gene-specific threshold, so the supplied generic ACMG/ClinGen-SVI default applies. The variant is absent from gnomAD v2.1 and v4.1, with observed frequency 0; the available non-cancer subset queries also record absence. Because 0 is below the generic BS1 threshold of 0.01, BS1 is not met.

Rule

{'source': 'generic ACMG/ClinGen-SVI default', 'threshold': 'allele frequency >= 0.01', 'threshold_publication': 'Whiffin et al. 2017, PMID:28518168', 'interpretation': 'Observed absence cannot meet BS1.'}

Evidence considered

• The NF1 ClinGen specification is the governing framework, but its retrieved ruleset provides no gene-specific BS1 threshold.
• gnomAD v2.1 reports the variant as absent in the all-comers dataset.
• gnomAD v4.1 reports the variant as absent in the all-comers dataset.
• The case evidence separately records the variant as absent from the queried gnomAD v2.1 non-cancer and v3.1 non-cancer subsets.
• The supplied generic BS1 default is allele frequency >=0.01; the case threshold block identifies this as the generic SVI default and cites Whiffin et al. 2017 (PMID:28518168).

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign assertion. The ClinVar query found no exact record for NM_001042492.2:c.2092_2093insT, with no variation ID, classification, review status, or expert-panel assertion. BP6 is therefore not met.

Rule

Apply only when the exact variant has a ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• ClinVar returned no exact match for NM_001042492.2:c.2092_2093insT; variation IDs, classification, review status, and submissions are absent.
• No expert-panel Benign or Likely benign ClinVar assertion is available to support BP6.

Sources

Reasoning

The NF1 ClinGen Neurofibromatosis and Schwannomatosis specification is available, but its retrieved rule payload is incomplete and contains no criterion-specific PS2 instruction. The case evidence does not document a confirmed de novo event: there is no proband-parent genotype comparison, parental testing result, confirmed maternity and paternity, or evidence excluding parental mosaicism. Therefore PS2 cannot be assessed.

Evidence considered

• The NF1 ClinGen specification is retrieved as Version 1.0, but the rule payload is empty/incomplete and provides no usable PS2-specific rule.
• The case materials do not document parental genotypes, a de novo determination, confirmed maternity/paternity, or testing designed to exclude parental mosaicism.

Still missing

• Parental testing results for the variant are not documented.
• Confirmed maternity and paternity are not documented.
• Parental mosaicism assessment is not documented.

Sources

Reasoning

The NF1 ClinGen Neurofibromatosis and Schwannomatosis specification was reviewed first, but its available ruleset contains no PS3-specific assay requirements or strength calibration. The reviewed functional literature includes protein-truncation, RNA, and cellular studies of NF1 at the gene or other-variant level, but none reports NM_001042492.2:c.2092_2093insT or NP_001035957.1:p.(Pro698LeufsTer2). Therefore, no validated variant-specific functional assay demonstrating a damaging effect, with appropriate controls and biologic relevance, is available to apply PS3. Gene-level evidence that NF1 loss of function is pathogenic cannot substitute for an assay of this variant.

Evidence considered

• The NF1 VCEP specification is present, but the available ruleset has an empty criteria/rule payload and does not provide PS3 assay requirements or strength calibration.
• PMID:10543400 evaluated NF1 transcript expression and protein truncation testing in patients with other truncating variants; the specified insertion was not reported.
• PMID:10862084 characterized NF1 mutation detection and a spectrum of other frameshift and splice variants; the specified insertion was not reported.
• PMID:12509763 describes the gene-level role of neurofibromin in RAS signaling without testing the specified variant.
• PMID:14722914 studied constitutional NF1 gene deletions rather than the specified insertion.
• PMID:19573811 studied NF1 inactivation in glioblastoma models and tumors without testing the specified insertion.

Still missing

• A validated variant-specific functional study is needed, such as RNA/protein analysis or a biologically relevant cellular assay with appropriate positive and negative controls.

Sources

Reasoning

The NF1 VCEP/CSPEC framework was retrieved but contains no criterion-level rules for PS4, and the available case evidence provides no exact-variant case series, case-control comparison, affected/unaffected counts, odds ratio, or other enrichment statistic. The literature extracts reviewed for the available papers do not report NM_001042492.2:c.2092_2093insT or p.(P698Lfs*2). Therefore PS4 cannot be assessed; no numeric threshold or comparison operator is available.

Evidence considered

• The retrieved NF1 CSPEC is incomplete and supplies no criterion-level PS4 rule.
• Available exact-variant literature extracts do not report NM_001042492.2:c.2092_2093insT or p.(P698Lfs*2).
• No case-control counts, odds ratio, likelihood ratio, or other variant-specific enrichment statistic is present in the reviewed case evidence.

Still missing

• Exact-variant affected-case and control counts or a validated case-control enrichment statistic
• The governing PS4 threshold and comparison operator, if NF1-specific

Sources

Reasoning

The NF1 ClinGen Neurofibromatosis and Schwannomatosis specification is available, but its retrieved rule payload is incomplete and contains no criterion-specific PM6 instruction. No de novo occurrence based only on parentage and phenotype, without molecular parental testing, is documented for this variant. The evidence contains no family report establishing a likely de novo event or meiosis-level support; therefore PM6 cannot be assessed.

Evidence considered

• The NF1 ClinGen specification is retrieved as Version 1.0, but the rule payload is empty/incomplete and provides no usable PM6-specific rule.
• The case materials do not document a family observation, parentage assessment, phenotype-supported de novo inference, or informative meioses for this variant.

Still missing

• A documented de novo case with credible parentage and phenotype information is absent.
• Parental testing or a documented rationale for untested parents is absent.
• The number of informative meioses is not documented.

Sources

Reasoning

The NF1 ClinGen Neurofibromatosis and Schwannomatosis specification is available, but its retrieved rule payload is incomplete and contains no criterion-specific PP1 instruction. The case evidence does not identify affected relatives carrying the variant, provide cosegregation across informative meioses, or describe phenotype consistency within a tested family. Consequently, segregation evidence is insufficient to assess PP1.

Evidence considered

• The NF1 ClinGen specification is retrieved as Version 1.0, but the rule payload is empty/incomplete and provides no usable PP1-specific rule.
• The case materials do not document affected relatives with the variant, family cosegregation, informative meioses, or phenotype consistency among carriers.

Still missing

• Affected relatives and their variant-testing results are not documented.
• The number of informative meioses is not documented.
• Phenotype consistency among variant-positive relatives is not documented.

Sources

Reasoning

The NF1 VCEP/CSPEC framework was retrieved but contains no criterion-level PP4 rule. The case materials do not provide the patient's clinical phenotype, a phenotype checklist, or a documented highly specific phenotype-to-disease match for NF1. General NF1 descriptions in literature are not evidence about this patient's phenotype. Therefore PP4 cannot be assessed.

Evidence considered

• The retrieved NF1 CSPEC is incomplete and supplies no criterion-level PP4 rule.
• The case evidence contains no patient phenotype or phenotype-specificity assessment.
• Gene-level descriptions of NF1 in the reviewed literature cannot establish PP4 for this individual.

Still missing

• Documented patient phenotype and relevant NF1 diagnostic features
• An applicable NF1-specific PP4 phenotype-specificity rule

Sources

Reasoning

BS2 requires observation of the variant in healthy individuals, typically including appropriate age and phenotype considerations for a dominant disorder, or relevant healthy homozygote observations where applicable. The available case evidence contains population absence results but no individual-level healthy-carrier observations, homozygote data, penetrance assessment, or age-qualified healthy cohort evidence for this variant. BS2 therefore cannot be assessed from the available evidence.

Rule

{'source': 'generic ACMG/AMP BS2 framework', 'interpretation': 'Requires qualifying observations in healthy individuals; population absence alone is insufficient.'}

Evidence considered

• The available gnomAD records report absence of the variant rather than observations in healthy carriers.
• No case-specific healthy-carrier, healthy-homozygote, age-at-observation, or penetrance data were identified.

Still missing

• Individual-level observations in healthy people with adequate age and phenotype assessment are unavailable.
• No healthy homozygote or penetrance-specific evidence is available for this variant.

Sources

Reasoning

The NF1 ClinGen Neurofibromatosis and Schwannomatosis specification was reviewed first, but its available ruleset contains no BS3-specific assay requirements or strength calibration. The reviewed functional literature does not report a validated benign-function assay for NM_001042492.2:c.2092_2093insT or NP_001035957.1:p.(Pro698LeufsTer2), and the gene-level or other-variant studies cannot establish that this frameshift has normal function. Accordingly, BS3 cannot be applied at any strength.

Evidence considered

• The NF1 VCEP specification is present, but the available ruleset has an empty criteria/rule payload and does not provide BS3 assay requirements or strength calibration.
• PMID:10543400 evaluated NF1 transcript expression and protein truncation testing in patients with other truncating variants; it did not demonstrate preserved function for the specified insertion.
• PMID:10862084 characterized NF1 mutation detection and other mutation classes; it did not test the specified insertion for benign function.
• PMID:12509763 provides gene-level RAS/neurofibromin biology without a benign-function assay for the specified variant.
• PMID:14722914 studied whole-gene NF1 deletions and is not evidence of benign function for the specified insertion.
• PMID:19573811 studied NF1 inactivation in glioblastoma models and tumors and provides no benign-function result for the specified insertion.

Still missing

• A validated variant-specific assay demonstrating preserved function, with appropriate controls and biologically relevant readout, is needed before BS3 can be considered.

Sources

Reasoning

The NF1 ClinGen Neurofibromatosis and Schwannomatosis specification is available, but its retrieved rule payload is incomplete and contains no criterion-specific BS4 instruction. No tested unaffected relative is documented as carrying the variant, and there is no family history, age-related penetrance assessment, or clinical evaluation sufficient to establish non-segregation. Therefore BS4 cannot be assessed.

Evidence considered

• The NF1 ClinGen specification is retrieved as Version 1.0, but the rule payload is empty/incomplete and provides no usable BS4-specific rule.
• The case materials do not document an unaffected confirmed carrier, clinical follow-up of relatives, or other evidence demonstrating non-segregation.

Still missing

• Unaffected relatives with confirmed variant carriage are not documented.
• Clinical evaluations and ages of potentially informative relatives are not documented.
• Family history and penetrance-relevant follow-up are not documented.

Sources

Reasoning

The governing NF1 specification establishes an autosomal dominant disease context, in which BP2 would require documented observation of the evaluated variant in trans with a pathogenic variant in an affected individual. The available case evidence contains no affected-proband observation, second pathogenic allele, parental testing, or phase information establishing such a configuration. Therefore BP2 cannot be assessed from the available evidence.

Rule

For an autosomal dominant disorder, assess BP2 only when the evaluated variant is documented in trans with a pathogenic variant in an affected individual; absent that observation and phase evidence, do not assess BP2.

Evidence considered

• The governing ClinGen NF1 specification lists neurofibromatosis type 1 as autosomal dominant.
• No affected-proband observation, pathogenic allelic partner, parental testing, or phase-resolved in-trans result is documented in the available case evidence.

Still missing

• Affected-proband genotype and phenotype documentation
• A documented pathogenic allelic partner
• Parental testing or other phase evidence establishing the variants are in trans

Sources

Reasoning

The NF1 VCEP/CSPEC framework was retrieved but contains no criterion-level BP5 rule. The available evidence does not document a second pathogenic variant, an established alternative molecular diagnosis, or the specific BP5 likelihood-ratio-style metric and threshold that would govern a numeric comparison. No BP5 conclusion can therefore be made.

Evidence considered

• The retrieved NF1 CSPEC is incomplete and supplies no criterion-level BP5 rule.
• The case evidence contains no documented alternative molecular diagnosis or second pathogenic variant that could establish BP5.
• No BP5 numeric value, threshold, or criterion-specific comparison operator is available; consequently no inequality can be evaluated.

Still missing

• Evidence for an alternative molecular diagnosis or second pathogenic variant explaining the phenotype
• The governing BP5 rule, including any metric, threshold, and literal comparison operator

Sources