Classification rationale

BS1BP4BP6 Likely Benign

BRAF c.483G>C

The BRAF c.483G>C (p.Leu161=) variant has not been identified as a statistically significant hotspot in Cancer Hotspots and has been reported in ClinVar as benign/likely benign, including a likely benign expert-panel classification.¹ This variant is present in gnomAD, with grpmax filtering allele frequency 0.03792% in v2.1 and 0.04133% in v4.1, which is above the BRAF VCEP BS1 threshold of 0.025% but below the BA1 threshold of 0.05%.² In silico splice prediction does not support a deleterious effect, with SpliceAI showing a maximum delta score of 0.02 for this synonymous change.³

BS1 + BP4 + BP6 → Likely Benign

1 hotspots ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗

Gene diagram · NM_001354609.1 · variants mapped to exon structure

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.97376e-05; MAF= 0.00297%, 48/1614116 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00054655; MAF= 0.05466%, 41/75016 alleles, homozygotes = 0); grpmax FAF= 0.00041326.

v2.1

This variant is present in gnomAD v2.1 (AF= 5.65731e-05; MAF= 0.00566%, 16/282820 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000600769; MAF= 0.06008%, 15/24968 alleles, homozygotes = 0); grpmax FAF= 0.00037921.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.003% · 48 / 1,614,116
0 hom · FAF 0.041%

African/African American 41 / 75,016	0.055%
Remaining individuals 5 / 62,510	0.008%
Admixed American 2 / 60,014	0.0033%

+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))

gnomAD v2.1

0.0057% · 16 / 282,820
0 hom · FAF 0.038%

African/African American 15 / 24,968	0.06%
Remaining individuals 1 / 7,222	0.014%

+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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