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 ↗

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.

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

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 14 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 · 3

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

The BRAF VCEP BS1 threshold is gnomAD filtering allele frequency >=0.025%. This variant exceeds that threshold in both population datasets, with grpmax FAF 0.03792% in gnomAD v2.1 and 0.04133% in gnomAD v4.1.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Available computational evidence supports no functional impact on splicing. SpliceAI predicts no significant splice effect for this synonymous variant, with a maximum delta score of 0.02.

cspec ↗spliceai ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.

ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant.

PS3 No approved functional study for this specific variant was identified to show a damaging effect on protein function or splicing.

PS4 No affected-proband series or case-control enrichment data were identified for this variant.

PM1 This variant is in exon 3 at p.Leu161=, which is outside the BRAF VCEP-listed PM1 regions (exon 6, exon 11, P-loop amino acids 459-474, and CR3 activation segment amino acids 594-627).

PM2 This variant is present in population databases and therefore is not absent from controls.

PM6 No presumed de novo occurrence with incomplete parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a deleterious splicing effect.

Benign

BA1 The BRAF VCEP BA1 threshold is gnomAD filtering allele frequency >=0.05%.

BS2 No data were identified showing this variant in well-phenotyped unaffected individuals sufficient for BS2 scoring.

BS4 No nonsegregation data were identified for this variant.

BP2 No evidence was identified that this variant occurs with an alternative molecular explanation in cis or trans sufficient for BP2 scoring.

BP5 No evidence was identified for an alternative molecular cause of disease sufficient for BP5 scoring.

BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but no nucleotide conservation evidence was identified to satisfy the full BP7 rule.

N/A · 11 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3

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

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