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 ↗

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

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 4 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= 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