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 ↗

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 · 5 applied · 11 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 · 5

Strength Supporting Moderate Strong Very strong

BA1 stand-alone review Benign

This variant exceeds the BRAF RASopathy VCEP BA1 population threshold of filtering allele frequency at or above 0.05%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BA1 threshold.

gnomAD v2.1 grpmax FAF 0.0015909 (0.15909%).gnomAD v4.1 grpmax FAF 0.00137943 (0.137943%).

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS1 strong review Benign

This variant exceeds the BRAF RASopathy VCEP BS1 population threshold of filtering allele frequency at or above 0.025%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BS1 threshold.

gnomAD v2.1 grpmax FAF 0.0015909 (0.15909%).gnomAD v4.1 grpmax FAF 0.00137943 (0.137943%).

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Available computational evidence predicts little or no splice effect. SpliceAI shows a maximum delta score of 0.16, which does not support a meaningful abnormal splicing outcome, so the in silico evidence supports BP4 for a splice-region variant in this VCEP framework.

SpliceAI DS_AG 0.00DS_AL 0.00DS_DG 0.16

cspec ↗spliceai ↗

BP6 supporting review Benign

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

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

cspec ↗clinvar ↗

BP7 supporting review Benign

This variant is a noncanonical intronic splice-region change at +3, and the BRAF RASopathy VCEP allows BP7 for intronic positions outside canonical splice sites when used with BP4. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.16, which supports BP7.

Variant position is +3 and therefore outside the canonical ±12 splice site.SpliceAI max delta score 0.16.

cspec ↗spliceai ↗

Assessed · not applied · 2 not met · 9 not assessed

Pathogenic

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

PS3 No approved functional or RNA study was identified for this exact variant showing abnormal splicing or another damaging effect.

PS4 This variant is reported in ClinVar, but no verified affected-case count, enrichment analysis, or VCEP point total was identified for this exact variant.

PM2 PM2 requires absence from gnomAD.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 For splicing impact, PP3 requires computational evidence supporting an abnormal outcome consistent with disease mechanism.

Benign

BS2 This variant is present in population databases, including one homozygote, but no confirmed unaffected clinical individuals meeting the RASopathy VCEP point-based BS2 framework were identified.

BS4 No segregation data showing lack of cosegregation were identified for this variant.

BP2 No evidence was identified showing this variant occurring with an alternative molecular explanation in the same gene that would support BP2 point assignment.

BP5 No evidence was identified showing a different molecular explanation for the phenotype in another gene or a phenotype fully explained by another cause.

N/A · 12 PVS1 · PS1 · PM1 · 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= 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.

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients fo

PMID 29398453 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP7 supporting

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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