Classification rationale

BP4BP6BS1BA1 Benign

BRAF c.1929A>G

The BRAF c.1929A>G (p.Gly643=) variant is reported in ClinVar as Benign with expert-panel review.¹ This variant is common in population databases, with an allele frequency of 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1, far above the RASopathy VCEP BA1 threshold of 0.05% and BS1 threshold of 0.025%.² Computational evidence does not support a damaging effect, with a REVEL score of 0.247 and SpliceAI predicting no significant splice impact with a maximum delta score of 0.01.³

BP4 + BP6 + BS1 + BA1 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 revelspliceai ↗cspec ↗

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= 0.178251; MAF= 17.82506%, 287439/1612556 alleles, homozygotes = 37917) and has highest observed frequency in the African/African American population (AF= 0.676837; MAF= 67.68368%, 50668/74860 alleles, homozygotes = 17235); grpmax FAF= 0.671898.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.211808; MAF= 21.18080%, 59743/282062 alleles, homozygotes = 10008) and has highest observed frequency in the African/African American population (AF= 0.678583; MAF= 67.85829%, 16894/24896 alleles, homozygotes = 5737); grpmax FAF= 0.669859.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

18% · 287439 / 1,612,556
37917 hom · FAF 67%

African/African American 50668 / 74,860	68% 17235 hom
Middle Eastern 1836 / 5,786	32% 330 hom
South Asian 28659 / 91,040	31% 4759 hom
Ashkenazi Jewish 6216 / 29,556	21% 680 hom
Remaining individuals 12595 / 62,418	20% 1501 hom
East Asian 7086 / 44,748	16% 620 hom
European (Finnish) 9213 / 63,930	14% 687 hom
European (non-Finnish) 163217 / 1,179,344	14% 11485 hom
Admixed American 7854 / 59,962	13% 618 hom
Amish 95 / 912	10% 2 hom

gnomAD v2.1

21% · 59743 / 282,062
10008 hom · FAF 67%

African/African American 16894 / 24,896	68% 5737 hom
South Asian 9619 / 30,588	31% 1619 hom
Ashkenazi Jewish 2175 / 10,362	21% 231 hom
East Asian 3750 / 19,946	19% 370 hom
Remaining individuals 1318 / 7,198	18% 154 hom
European (Finnish) 3751 / 25,082	15% 292 hom
European (non-Finnish) 18559 / 128,644	14% 1418 hom
Admixed American 3677 / 35,346	10% 187 hom

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (13 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40391)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.247.

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 previously been reported in somatic cancers (COSMIC; COSV56058907, n = 37 times).

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

Triaged references · 6 PMIDs not cited in assessment

24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

20301303 ↗ Noonan Syndrome. CLINVAR

20301557 ↗ Noonan Syndrome with Multiple Lentigines. CLINVAR

20876176 ↗ Noonan syndrome: clinical features, diagnosis, and management guidelines. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR