NM_001354609.1:c.1406G>A

BRAF · NP_001341538.1:p.(Gly469Glu) · NM_001354609.1

GRCh37: chr7:140481402 C>T · GRCh38: chr7:140781602 C>T

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PS3 moderate PM1 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Gly469Glu)

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.1406G>A (p.Gly469Glu) variant has been observed in somatic cancers and has been reported in ClinVar with an expert panel pathogenic classification.

This variant is absent from gnomAD v2.1 (0/251420 alleles), gnomAD v4.1 (0/1614020 alleles), and gnomAD-Canada, which supports rarity in population databases.

In the RASopathy VCEP approved functional-study resource, p.Gly469Glu is listed as a pathogenic BRAF control in both MEK activation and ERK activation assays, and a published functional study showed constitutive ERK phosphorylation with low MEK phosphorylation, consistent with abnormal pathway activation.

Computational data support a damaging missense effect, with REVEL 0.949 above the PP3 threshold, BayesDel 0.454064, and no predicted splice disruption by SpliceAI (max delta score 0.00).

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, and the BRAF RASopathy specification marks PVS1 as not applicable. The generic PVS1 scaffold also indicates that this variant does not fall into a null-variant category.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously established pathogenic variant producing the same amino acid change by a different nucleotide change, or a verified analogous RAF1/BRAF residue match, was confirmed in the inspected evidence.	cspec vcep_raf_alignment
PS2	Not assessed	Published CFC data indicate that BRAF-related cases are often de novo, but confirmed de novo status with the point-based PS2 evidence required for this specific variant was not verified from the inspected evidence.	cspec PMID:16439621 clinvar
PS3	Met	In the RASopathy VCEP approved functional-study resource, p.Gly469Glu is listed as a pathogenic BRAF control in both MEK activation and ERK activation assays, meeting the two-assay threshold for PS3_Moderate. In a published functional study, G469E-mutant melanoma cells showed constitutive ERK phosphorylation with low MEK phosphorylation, consistent with abnormal CRAF-dependent pathway activation.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:18794803
PS4	Not assessed	This variant has been reported clinically, but the exact number of unrelated affected individuals and the RASopathy VCEP point-based PS4 score were not verified from the inspected evidence.	cspec clinvar
PM1	Met	p.Gly469Glu lies in the BRAF P-loop (amino acids 459-474), which the BRAF RASopathy specification designates as a critical and well-established functional domain for PM1 at moderate strength.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 (0/251420 alleles) and gnomAD v4.1 (0/1614020 alleles), which meets the BRAF RASopathy PM2_Supporting requirement of absence from gnomAD. It is also absent from gnomAD-Canada.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	The BRAF RASopathy specification marks PM3 as not applicable for this gene-disease context.	cspec
PM4	N/A	This is a missense substitution and does not change protein length, so PM4 is not applicable.	cspec
PM5	Not assessed	The BRAF RASopathy framework uses classic same-residue PM5 logic, but no verified same-codon pathogenic comparator was confirmed from the inspected evidence for this review.	cspec pm5_candidates
PM6	Not assessed	A sporadic or assumed de novo occurrence for this exact variant was not verified well enough to assign PM6 under the point-based RASopathy framework.	cspec PMID:16439621 clinvar
PP1	Not assessed	No segregation data were identified that establish co-segregation of this variant with disease across the informative meioses required by the RASopathy framework.	cspec
PP2	Not assessed	The BRAF RASopathy specification allows PP2 when the missense z score is greater than 3.09, but a missense constraint z score was not verified in the inspected evidence.	cspec
PP3	Met	For this missense variant, REVEL is 0.949, which is above the BRAF RASopathy PP3 threshold of 0.7. BayesDel is also positive at 0.454064, while SpliceAI shows no meaningful splice effect (max delta score 0.00), supporting a pathogenic missense effect rather than a splice-driven mechanism.	cspec revel bayesdel spliceai
PP4	N/A	The BRAF RASopathy specification marks PP4 as not applicable.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant does not meet BA1 because it is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BRAF RASopathy BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant does not meet BS1 because it is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BRAF RASopathy BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observations in unaffected individuals were identified to support BS2 under the RASopathy point-based framework.	cspec
BS3	N/A	The BRAF RASopathy specification marks BS3 as not applicable.	cspec
BS4	Not assessed	No non-segregation evidence was identified for this variant, so BS4 cannot be assessed.	cspec
BP1	N/A	In the BRAF RASopathy framework, BP1 is adapted for truncating variants in a gain-of-function disease context. This variant is missense, so BP1 is not applicable.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with another established pathogenic variant.	cspec
BP3	N/A	The BRAF RASopathy specification marks BP3 as not applicable.	cspec
BP4	Not met	This missense variant does not meet BP4 because REVEL is 0.949, which is above the benign-supporting threshold of 0.3. SpliceAI predicts no significant splice impact (max delta score 0.00), but the missense prediction profile does not support a benign interpretation.	cspec revel spliceai bayesdel
BP5	Not assessed	No alternate molecular explanation with the point-based evidence required for BP5 was identified.	cspec
BP6	N/A	The BRAF RASopathy specification marks BP6 as not applicable.	cspec
BP7	N/A	This is not a synonymous or non-coding splice-region variant, so BP7 is not applicable.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.