Starting

Initialising…

NF1

Final classification

VUS

NF1 c.2033C>T · p.Pro678Leu

NF1

The NF1 c.2033C>T (p.Pro678Leu) variant has been reported in ClinVar, where most submissions classify it as likely benign or benign, with one submission classifying it as uncertain significance.

Gene

NF1

Transcript

NM_000267.3

HGVS · transcript:coding

NM_000267.3:c.2033C>T

Consequence

N/A

GRCh38

chr17:31226466 C>T

GRCh37

chr17:29553484 C>T

Basis 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: BP4 supporting; combination = 1 supporting benign, which maps to VUS. ▾

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: BP4 supporting; combination = 1 supporting benign, which maps to VUS.

Classification rationale

BP4 VUS

NF1 c.2033C>T

The NF1 c.2033C>T (p.Pro678Leu) variant has been reported in ClinVar, where most submissions classify it as likely benign or benign, with one submission classifying it as uncertain significance.¹ This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 229/1613768 alleles overall (AF 0.01419%), with the highest observed frequency in the African/African American population at 139/75006 alleles (AF 0.18532%) and one homozygote reported.² Available computational evidence supports no meaningful functional impact, with SpliceAI showing no predicted splice effect (maximum delta score 0.00), REVEL at 0.141, and BayesDel at -0.334865.³

BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

Gene diagram · NM_000267.3 · variants mapped to exon structure

NF1 NM_000267.3

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000141904; MAF= 0.01419%, 229/1613768 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00185319; MAF= 0.18532%, 139/75006 alleles, homozygotes = 0); grpmax FAF= 0.00160212.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.014% · 229 / 1,613,768
1 hom · FAF 0.16%

African/African American 139 / 75,006	0.19%
East Asian 32 / 44,880	0.071%
Remaining individuals 16 / 62,480	0.026%
South Asian 21 / 91,064	0.023% 1 hom
Admixed American 9 / 59,964	0.015%
European (non-Finnish) 12 / 1,179,796	0.001%

+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.141. BayesDel score = -0.334865.

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; COSV62204740, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots