NM_001042492.2:c.6776T>C (p.Val2259Ala) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).1 Multiple in silico predictors suggest a neutral effect: REVEL score 0.29, BayesDel score -0.045, and SpliceAI max delta 0.08 (BP4_Supporting).2 ClinVar classifies this variant as Uncertain Significance (VariationID 826571, 1 clinical laboratory, criteria provided, single submitter).3 No variant-specific functional studies, de novo observations, segregation data, or case-control evidence were identified for this variant.4 With PM2 (supporting pathogenic) and BP4 (supporting benign) as the only met criteria, the evidence is insufficient to classify beyond Uncertain Significance. This classification is consistent with the existing ClinVar entry.5
NF1
Final classification
VUS
PM2BP4
NF1
c.6776T>C
p.Val2259Ala
This variant
NM_001042492.2:c.6776T>C (p.Val2259Ala) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).
Neurofibromatosis and Schwannomatosis Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
NF1 c.6776T>C
PM2 + BP4
→
VUS
Gene diagram
· NM_001042492.2 · variants mapped to exon structure
NF1
NM_001042492.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 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
NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0). The variant meets PM2 at supporting level: absent from large population databases (AF < 0.1%).
Absent from gnomAD v2.1v4.1and gnomAD-Canada (AF=0).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious effect: REVEL score 0.29 (below 0.5 threshold, predicting neutral), BayesDel score -0.045 (benign-leaning), and SpliceAI max delta score 0.08 (no predicted splice impact).
REVEL 0.29 (neutral)BayesDel -0.045 (benign-leaning)SpliceAI 0.08 (no splice impact).
Assessed · not applied
· 6 not met · 12 not assessed
Pathogenic
PS2
No de novo data are available for NM_001042492.2:c.6776T>C.
PS3
No variant-specific functional studies demonstrating a damaging effect for NM_001042492.2:c.6776T>C (p.Val2259Ala) were identified.
PS4
No case-control or variant-specific prevalence data are available for NM_001042492.2:c.6776T>C.
PM1
NM_001042492.2:c.6776T>C (p.Val2259Ala) is not located in a statistically significant mutational hotspot per CancerHotspots.org, nor within the well-established NF1 GRD (GAP-related domain, residues ~1198–1530).
PM6
No de novo data are available for NM_001042492.2:c.6776T>C.
PP1
No cosegregation data are available for NM_001042492.2:c.6776T>C.
PP2
No gene-level missense constraint metrics (e.g., missense Z-score, HCI prior) were available for NF1 NM_001042492.2 to support PP2 application for this variant.
PP3
Multiple in silico predictors do not support a deleterious effect: REVEL score 0.29 (below 0.5 threshold), BayesDel score -0.045 (benign-leaning), and SpliceAI max delta score 0.08 (no predicted splice impact).
PP4
No phenotype or clinical data are available for the proband carrying NM_001042492.2:c.6776T>C.
PP5
NM_001042492.2:c.6776T>C is classified as Uncertain Significance in ClinVar (VariationID 826571, 1 clinical laboratory, review status: criteria provided, single submitter).
Benign
BA1
NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0).
BS1
NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0).
BS2
No data are available regarding observation of NM_001042492.2:c.6776T>C in healthy adult individuals for a fully penetrant dominant disorder.
BS3
No variant-specific functional studies demonstrating no damaging effect for NM_001042492.2:c.6776T>C (p.Val2259Ala) were identified.
BS4
No non-segregation data are available for NM_001042492.2:c.6776T>C.
BP2
No data are available regarding observation of NM_001042492.2:c.6776T>C in trans with a pathogenic NF1 variant.
BP5
No data are available regarding identification of NM_001042492.2:c.6776T>C in a case with an alternate molecular basis for disease.
BP6
NM_001042492.2:c.6776T>C is classified as Uncertain Significance in ClinVar (VariationID 826571).
N/A · 5
PVS1 · PS1 · PM5 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 826571)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.29. BayesDel score = -0.045496.
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.
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; COSV106479531, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 1 PMID not cited in assessment
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.
CLINVAR