Classification rationale

PM2 BP4 VUS

NF1 c.2573C>G missense · exon 21

PM2 (Supporting): extremely rare in population databases, with highest allele frequency 0.00143% in gnomAD v4.1, below the 0.1% threshold. BP4 (Supporting): REVEL 0.042 is at or below the benign-supporting threshold, and SpliceAI max delta 0.00 predicts no splice impact. Overall classification: VUS - one pathogenic-supporting (PM2) and one benign-supporting (BP4) criterion meet no combination threshold under the generic ACMG/AMP 2015 framework.

PM2 + BP4 → VUS

Gene diagram · NM_001042492.3 · variants mapped to exon structure

NF1 NM_001042492.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met (Supporting): extremely rare in population databases, with highest allele frequency 0.00143% (23/1,611,856 alleles) in gnomAD v4.1, below the 0.1% threshold.

The NF1 ClinGen/CSPEC record was checked first, but no criterion-level PM2 rule was retrieved; generic ACMG/AMP PM2 guidance was applied.gnomAD v4.1 reports AF 1.42693e-05 (0.00143%), 23/1,611,856 alleles, and zero homozygotes; the highest listed subgroup AF is 1.94942e-05 (0.00195%).gnomAD v2.1 reports AF 2.3921e-05 (0.00239%), 6/250,826 alleles, and zero homozygotes.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 supporting Benign

Met (Supporting): REVEL 0.042 is at or below the benign-supporting threshold, and SpliceAI max delta 0.00 predicts no splice impact.

The available NF1 CSPEC framework is incomplete and contains no PP3/BP4-specific rule payload, gene-specific computational lookup, or pre-assigned criterion for this variant.REVEL score is 0.042. The ClinGen SVI calibrated REVEL thresholds published in PMID:36413997 use REVEL >=0.70 for PP3 and <=0.15 for BP4; 0.042 meets the BP4 threshold.SpliceAI Lookup reports a maximum delta score of 0.00 and predicts no significant splice impact for NM_001042492.3:c.2573C>G.

cspec ↗spliceai ↗

Assessed · not applied · 5 not met · 16 not assessed

Pathogenic

PS1 Not assessed: no validated pathogenic or likely pathogenic same-amino-acid substitution at residue 858 was available for comparison.

PS2 Not assessed: no de novo observation with parental testing documenting absence of the variant in both biological parents was available.

PS3 Not assessed: no variant-specific functional assay demonstrating a deleterious effect was available.

PS4 Not assessed: no variant-specific case-control or cohort enrichment data were available.

PM1 Not assessed: the authoritative NF1 domain list required for a residue-based mutational-hotspot check was unavailable.

PM5 Not assessed: no validated pathogenic missense comparator at residue 858 was available.

PM6 Not assessed: no documented presumed de novo occurrence with family and phenotype details was available.

PP1 Not assessed: no segregation data in affected or unaffected relatives were available.

PP2 Not assessed: the NF1 specification provides no PP2 rule establishing missense as a common pathogenic mechanism.

PP3 Not met: REVEL 0.042 is below the pathogenic-supporting threshold, and SpliceAI max delta 0.00 predicts no splice impact.

PP4 Not assessed: no proband phenotype or phenotype-specificity evidence was provided.

PP5 Not met: no ClinVar expert-panel pathogenic or likely pathogenic classification exists for this exact variant.

Benign

BA1 Not met: highest observed population frequency is 0.00143%, far below the 1% benign stand-alone threshold.

BS1 Not met: highest subgroup frequency is 0.00195% in gnomAD v4.1, far below the 0.3% benign-frequency threshold.

BS2 Not assessed: no healthy adult carriers were documented, and absence of homozygotes is not positive evidence.

BS3 Not assessed: no variant-specific functional assay demonstrating preserved NF1 function was available.

BS4 Not assessed: no unaffected relatives carrying the variant or pedigree-based non-segregation evidence were documented.

BP1 Not assessed: the NF1 specification provides no BP1 rule, and missense is not established as a generally non-pathogenic mechanism in NF1.

BP2 Not assessed: a ClinVar note reports co-occurrence with an NF1 truncating variant, but phase (trans/cis) and individual-level records were not established.

BP5 Not assessed: no evidence of an independently pathogenic molecular diagnosis fully explaining the phenotype was available.

BP6 Not met: no ClinVar expert-panel benign or likely benign classification exists for this exact variant.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.42693e-05; MAF= 0.00143%, 23/1611856 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.94942e-05; MAF= 0.00195%, 23/1179836 alleles, homozygotes = 0); grpmax FAF= 1.298e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.3921e-05; MAF= 0.00239%, 6/250826 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.29811e-05; MAF= 0.00530%, 6/113248 alleles, homozygotes = 0); grpmax FAF= 2.301e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0014% · 23 / 1,611,856
0 hom · FAF 0.0013%

European (non-Finnish)

23 / 1,179,836

0.0019%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0024% · 6 / 250,826
0 hom · FAF 0.0023%

European (non-Finnish)

6 / 113,248

0.0053%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 185364)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.042. BayesDel score = -0.546775.

SpliceAI ↗

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. NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107423130, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

17636453 ↗ Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors. CLINVAR

20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR

20301471 ↗ Wilms Tumor Predisposition. CLINVAR

26324357 ↗ American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

33939658 ↗ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. CLINVAR