Variant classification summary

NM_001042492.2:c.2092_2093insT

NF1 · NP_001035957.1:p.(Pro698LeufsTer2) · NM_001042492.2

GRCh37: chr17:29553543 C>CT · GRCh38: chr17:31226525 C>CT

Gene: NF1 Transcript: NM_001042492.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Pro698LeufsTer2)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the exon 18 frameshift predicts p.(Pro698LeufsTer2), truncating NF1 at residue 699 of 2,840.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, with observed allele frequency 0.

3

Likely Pathogenic: PVS1 very strong plus PM2 supporting meet the applicable PVS1-plus-supporting combination addendum.

Final determination: With no usable NF1-specific final-classification rule, the generic fallback applies: PVS1 at very strong plus one supporting criterion, PM2, yields Likely Pathogenic under the ClinGen SVI PVS1-plus-supporting addendum.

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	Met	Met at very strong: the exon 18 frameshift predicts p.(Pro698LeufsTer2), truncating NF1 at residue 699 of 2,840 with many downstream coding exons remaining.	cspec pvs1_generic_framework
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented proband-parent genotype comparison or confirmed de novo status is available for this NF1 frameshift variant.	cspec
PS3	Not assessed	Not assessed: no validated functional assay for NF1 c.2092_2093insT or p.(Pro698LeufsTer2) was reported in the reviewed sources.	cspec PMID:10543400 PMID:10862084 PMID:12509763 PMID:14722914 PMID:19573811
PS4	Not assessed	Not assessed: no exact-variant case-control counts, enrichment statistic, or applicable PS4 threshold is available.	cspec
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: observed frequency 0 in gnomAD v2.1 and v4.1 is below the PM2 threshold of 0.0001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: NF1 is specified as autosomal dominant, so the recessive in-trans affected-individual criterion does not apply.	cspec
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no likely de novo occurrence based on parentage and phenotype is documented, and no meiosis or family evidence is available.	cspec
PP1	Not assessed	Not assessed: no affected-relative carrier data or informative cosegregation across meioses is documented for this NF1 variant.	cspec
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: this frameshift is outside PP3's calibrated missense and intronic/splice-region predictor scope.	cspec
PP4	Not assessed	Not assessed: the patient's phenotype and a disease-specific phenotype match are not documented in the available evidence.	cspec
PP5	Not met	Not met: ClinVar reports no exact-variant expert-panel Pathogenic or Likely pathogenic assertion for c.2092_2093insT.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 below the 0.05 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show observed frequency 0, below the generic BS1 threshold of 0.01.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no age-qualified healthy carriers, healthy homozygotes, penetrance data, or individual-level BS2 evidence are reported.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign-function assay for NF1 c.2092_2093insT or p.(Pro698LeufsTer2) was reported in the reviewed sources.	cspec PMID:10543400 PMID:10862084 PMID:12509763 PMID:14722914 PMID:19573811
BS4	Not assessed	Not assessed: no unaffected relative with confirmed variant carriage and adequate clinical evaluation is documented to demonstrate non-segregation.	cspec
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no affected-proband observation or phase-resolved pathogenic allelic partner is documented for the required in-trans BP2 configuration.	cspec
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: this frameshift is outside BP4's calibrated missense and intronic/splice-region predictor scope.	cspec
BP5	Not assessed	Not assessed: no alternative molecular diagnosis or applicable BP5 rule, metric, threshold, and operator is documented.	cspec
BP6	Not met	Not met: ClinVar reports no exact-variant expert-panel Benign or Likely benign assertion for c.2092_2093insT.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001042492.2:c.2092_2093insT in NF1 is a frameshift variant predicted to produce NP_001035957.1:p.(Pro698LeufsTer2). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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