Classification rationale

BA1BS1BP4BP6 Benign

BRAF c.708C>T

The BRAF c.708C>T (p.Asn236=) variant has been reported in ClinVar as benign, including a benign expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is present in population databases above the BRAF RASopathy VCEP BA1 threshold of 0.05%, with a grpmax filtering allele frequency of 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1; the highest observed population frequency is in South Asian individuals at 0.17678% in gnomAD v2.1 and 0.14861% in gnomAD v4.1.² This is a synonymous variant, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, supporting no meaningful impact on splicing.³

BA1 + BS1 + BP4 + BP6 → Benign

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗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 · 4 applied · 13 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

Population frequency exceeds the RASopathy VCEP BA1 threshold of 0.05%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.05% threshold.

gnomAD v2.1 grpmax FAF 0.00139101 (0.13910%).gnomAD v4.1 grpmax FAF 0.0012819 (0.12819%).

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS1 strong Benign

Population frequency exceeds the RASopathy VCEP BS1 threshold of 0.025%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.025% threshold.

gnomAD v2.1 grpmax FAF 0.00139101 (0.13910%).gnomAD v4.1 grpmax FAF 0.0012819 (0.12819%).

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Computational evidence supports no meaningful effect. This synonymous variant has no applicable REVEL score, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, which is consistent with negligible splicing effect.

SpliceAI max delta score 0.06.Variant is synonymous.

cspec ↗spliceai ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.

The BRAF RASopathy VCEP marks BP6 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 3 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence.

PS3 No approved functional study for this exact variant was identified, so PS3 cannot be applied.

PS4 No case-enrichment or point-based affected-individual evidence was identified for this variant, and the variant is not absent from population databases, so PS4 cannot be applied.

PM1 This variant is in exon 5 at codon 236, which is outside the BRAF RASopathy VCEP PM1 regions limited to exon 6, exon 11, the P-loop (amino acids 459-474), and the CR3 activation segment (amino acids 594-627).

PM2 This variant is present in gnomAD, so it does not meet the PM2 requirement for absence from controls.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 cannot be applied from the available evidence.

PP1 No segregation data were identified for this variant, so PP1 cannot be applied.

PP3 Computational evidence does not support a deleterious effect.

Benign

BS2 Population observations were identified, including rare homozygotes in gnomAD, but no phenotype-confirmed unaffected-case evidence was identified to score BS2 under the RASopathy VCEP point system.

BS4 No informative non-segregation data were identified for this variant, so BS4 cannot be applied.

BP2 No evidence of an alternative molecular cause in the same gene or phasing information relevant to BP2 was identified.

BP5 No alternative molecular diagnosis in a different gene or phenotype explanation relevant to BP5 was identified.

BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, but the available evidence reviewed here did not establish whether the altered nucleotide is not highly conserved, so BP7 was not fully assessed.

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= 0.00013504; MAF= 0.01350%, 217/1606934 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00148613; MAF= 0.14861%, 135/90840 alleles, homozygotes = 2); grpmax FAF= 0.0012819.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000255343; MAF= 0.02553%, 72/281974 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00176783; MAF= 0.17678%, 54/30546 alleles, homozygotes = 1); grpmax FAF= 0.00139101.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.014% · 217 / 1,606,934
2 hom · FAF 0.13%

South Asian 135 / 90,840	0.15% 2 hom
Middle Eastern 6 / 6,046	0.099%
Remaining individuals 25 / 62,274	0.04%
East Asian 3 / 44,768	0.0067%
African/African American 4 / 74,766	0.0054%
European (non-Finnish) 41 / 1,174,086	0.0035%
Ashkenazi Jewish 1 / 29,546	0.0034%
Admixed American 2 / 59,950	0.0033%

+ 2 not observed (European (Finnish), Amish)

gnomAD v2.1

0.026% · 72 / 281,974
1 hom · FAF 0.14%

South Asian 54 / 30,546	0.18% 1 hom
East Asian 3 / 19,940	0.015%
Remaining individuals 1 / 7,190	0.014%
Ashkenazi Jewish 1 / 10,356	0.0097%
European (non-Finnish) 12 / 128,658	0.0093%
Admixed American 1 / 35,354	0.0028%

+ 2 not observed (African/African American, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (3 clinical laboratories) and as 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 = 0.06).

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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