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NF1c.6776T>CUncertain significance
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Variant interpretation report

NF1 c.6776T>C, p.(Val2259Ala)

NM_001042492.2:c.6776T>C NP_001035957.1:p.(Val2259Ala) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About NF1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen NF1 VCEP v1.0.0. 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.080 maximum delta

Recorded SpliceAI maximum delta score: 0.080. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance.

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV106479531, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen NF1 VCEP v1.0.0, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 6 not met · 12 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001042492.2:c.6776T>C (p.Val2259Ala) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).

Multiple in silico predictors suggest a neutral effect: REVEL score 0.29, BayesDel score -0.045, and SpliceAI max delta 0.08 (BP4_Supporting).

ClinVar classifies this variant as Uncertain Significance (VariationID 826571, 1 clinical laboratory, criteria provided, single submitter).

No variant-specific functional studies, de novo observations, segregation data, or case-control evidence were identified for this variant.

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.

Met · 2

PM2 SupportingNM_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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada (AF=0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.29 (neutral)
  • BayesDel -0.045 (benign-leaning)
  • SpliceAI 0.08 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 6 · evaluated, threshold not reached

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). Position 2259 lies near the C-terminal domain boundary without functional domain assignment supporting PM1. Details ▾Hide ▴
Evidence considered
  • Not in a statistically significant hotspot
  • falls outside the GRD critical functional domain.
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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.29 (neutral)
  • BayesDel -0.045 (benign-leaning)
  • SpliceAI 0.08 (no splice impact).
Sources
revelbayesdelspliceai ↗
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). No reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS
  • single submitter. No expert panel or multi-submitter pathogenic classification.
Sources
clinvar ↗
BA1 NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0). Does not meet the >1% allele frequency threshold for BA1. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations (AF=0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 NM_001042492.2:c.6776T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0). Does not meet the >0.3% allele frequency threshold for BS1. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations (AF=0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP6 NM_001042492.2:c.6776T>C is classified as Uncertain Significance in ClinVar (VariationID 826571). No reputable source has reported this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS
  • not reported as benign by any submitter.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS2 No de novo data are available for NM_001042492.2:c.6776T>C. Details ▾Hide ▴
Evidence considered
  • No de novo observations were identified in the evidence reviewed.
Still missing
  • De novo testing data not available for this variant.
PS3 No variant-specific functional studies demonstrating a damaging effect for NM_001042492.2:c.6776T>C (p.Val2259Ala) were identified. OncoKB classifies this variant as having Unknown Oncogenic Effect. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence.
Still missing
  • No functional assays (e.g.
  • GTPase activity
  • RAS signaling) have been reported for this specific missense change.
Sources
oncokb ↗
PS4 No case-control or variant-specific prevalence data are available for NM_001042492.2:c.6776T>C. The single ClinVar submission (VUS, 1 laboratory) does not provide proband counts or phenotype details. Details ▾Hide ▴
Evidence considered
  • ClinVar: single submitter VUS
  • no proband counts or case-control data.
Still missing
  • No published proband counts or case-control studies for this variant.
Sources
clinvar ↗
PM6 No de novo data are available for NM_001042492.2:c.6776T>C. Details ▾Hide ▴
Evidence considered
  • No de novo observations identified.
Still missing
  • De novo testing data not available.
PP1 No cosegregation data are available for NM_001042492.2:c.6776T>C. Details ▾Hide ▴
Evidence considered
  • No segregation data identified.
Still missing
  • Segregation analysis not available for this variant.
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. Details ▾Hide ▴
Evidence considered
  • HCI prior not found
  • no missense constraint data available.
Still missing
  • No gnomAD missense constraint Z-score or HCI prior score available.
PP4 No phenotype or clinical data are available for the proband carrying NM_001042492.2:c.6776T>C. Details ▾Hide ▴
Evidence considered
  • No proband phenotype data available.
Still missing
  • Proband phenotype information not provided.
BS2 No data are available regarding observation of NM_001042492.2:c.6776T>C in healthy adult individuals for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
  • No healthy control data available.
Still missing
  • No data on observation in healthy controls.
BS3 No variant-specific functional studies demonstrating no damaging effect for NM_001042492.2:c.6776T>C (p.Val2259Ala) were identified. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies showing benign effect.
Still missing
  • No functional studies have been reported for this specific missense change.
Sources
oncokb ↗
BS4 No non-segregation data are available for NM_001042492.2:c.6776T>C. Details ▾Hide ▴
Evidence considered
  • No segregation data identified.
Still missing
  • Segregation analysis not available.
BP2 No data are available regarding observation of NM_001042492.2:c.6776T>C in trans with a pathogenic NF1 variant. Details ▾Hide ▴
Evidence considered
  • No trans observation data available.
Still missing
  • No data on co-occurrence with a pathogenic variant in trans.
BP5 No data are available regarding identification of NM_001042492.2:c.6776T>C in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Still missing
  • No data on co-occurrence with an alternate molecular cause.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_001042492.2:c.6776T>C is a missense variant (p.Val2259Ala), which does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a null variant
  • PVS1 variant assessment confirms ineligible bucket.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo pathogenic variant with the same amino acid change at the same position has been identified as a comparator for PS1 application. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator available.
PM5 N/ANo pathogenic missense variant at the same amino acid residue (p.Val2259) was identified as a comparator for PM5 application. Automated candidate harvesting returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator identified in ClinVar.
Sources
pm5_candidates
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant mechanism, when the variant is observed in trans with a pathogenic variant. Neither a truncating mechanism predominance determination nor trans observation data are available for this variant; additionally, missense variants are a recognized disease mechanism in NF1. Details ▾Hide ▴
Evidence considered
  • Missense variants are a known disease mechanism in NF1
  • no trans data available.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001042492.2:c.6776T>C is a missense variant (p.Val2259Ala), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.
PS5 N/APS5 is not defined in the generic ACMG/AMP 2015 framework (PMID:25741868) and the NF1 VCEP criteria set (version 1.0.0) contains no rule payload to support application of this criterion. Details ▾Hide ▴
Evidence considered
  • NF1 VCEP framework is empty
  • generic ACMG/AMP does not include PS5.
Sources
cspec ↗final_classification_framework

Identifiers

Gene
NF1
Transcript
NM_001042492.2
Coding (HGVS c.)
NM_001042492.2:c.6776T>C
Protein (HGVS p.)
NP_001035957.1:p.(Val2259Ala)
GRCh38
chr17:31338096 T>C
GRCh37
chr17:29665114 T>C
ClinVar
826571
COSMIC
COSV106479531

Gene diagram

Every interpreted variant in NF1, mapped onto the exon structure of NM_001042492.2. Select a row to find it on the plot.

NF1NM_001042492.2
Fetching transcript structure from UCSC…
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

SpliceAI acceptor lossat +43 bp
0.000
SpliceAI acceptor gainat -71 bp
0.080
SpliceAI donor lossat -485 bp
0.000
SpliceAI donor gainat +43 bp
0.060
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.170

Other predictors

REVEL
0.290
BayesDel
-0.045

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.29 (neutral)
  • BayesDel -0.045 (benign-leaning)
  • SpliceAI 0.08 (no splice impact).
Sources
revelbayesdelspliceai ↗
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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.29 (neutral)
  • BayesDel -0.045 (benign-leaning)
  • SpliceAI 0.08 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001042492.2:c.6776T>C is a missense variant (p.Val2259Ala), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.29. BayesDel score = -0.045496.

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

  • 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. · 2015
    A practice guideline from ACMG and NSGC providing referral indications for cancer predisposition assessment. NF1 is mentioned in syndrome tables and differentials. NM_001042492.2:c.6776T>C (p.Val2259Ala) was not identified in this paper.
    Does not name this variant
    PMID 25394175 ↗

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 0.080 Open source ↗
ClinVar 1 Uncertain significance 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 ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

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

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV106479531, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.