Classification rationale

BA1BS1BP4BP6BP7 Benign

BRAF c.2127+3A>G

The BRAF c.2127+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as benign or likely benign, including a benign expert-panel classification.¹ This variant is present in population databases at a frequency above the BRAF RASopathy VCEP benign thresholds, with grpmax filtering allele frequencies of 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1.² SpliceAI predicts no significant splice impact for this intronic +3 variant, with a maximum delta score of 0.16, which does not support a deleterious splicing effect and is consistent with BP4 and BP7 in this framework.³

BA1 + BS1 + BP4 + BP6 + BP7 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 5 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= 9.42871e-05; MAF= 0.00943%, 152/1612098 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00161351; MAF= 0.16135%, 121/74992 alleles, homozygotes = 1); grpmax FAF= 0.00137943.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000176897; MAF= 0.01769%, 50/282650 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0017222; MAF= 0.17222%, 43/24968 alleles, homozygotes = 1); grpmax FAF= 0.0015909.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0094% · 152 / 1,612,098
1 hom · FAF 0.14%

African/African American 121 / 74,992	0.16% 1 hom
Middle Eastern 1 / 4,552	0.022%
Admixed American 10 / 60,026	0.017%
Remaining individuals 9 / 62,340	0.014%
European (non-Finnish) 11 / 1,179,932	0.00093%

+ 5 not observed (European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.018% · 50 / 282,650
1 hom · FAF 0.16%

African/African American 43 / 24,968	0.17% 1 hom
Admixed American 5 / 35,426	0.014%
European (non-Finnish) 2 / 129,056	0.0015%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

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 = 0.16).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID PMID:29398453

PMID PMID:29398453 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP7 supports · met

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC