Variant classification summary

NM_001354609.1:c.1799T>G

BRAF · NP_001341538.1:p.(Val600Gly) · NM_001354609.1

GRCh37: chr7:140453136 A>C · GRCh38: chr7:140753336 A>C

Gene: BRAF Transcript: NM_001354609.1

Final call

Likely Pathogenic

PS3 supporting PM1 moderate PM2 supporting PM5 moderate PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Val600Gly)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.1799T>G (p.Val600Gly, p.V600G) variant has been observed in somatic cancers, including 27 occurrences in COSMIC, and has been reported in ClinVar with a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population reference datasets.

3

In a published functional study, p.Val600Gly increased ERK and ELK phosphorylation relative to wild type, consistent with an activating effect; the BRAF RASopathy functional-study framework supports PS3 at supporting strength when one approved assay is available.

4

Computational evidence supports a damaging missense effect, with REVEL 0.925 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.357299, and SpliceAI showing no major splice effect with a maximum delta score of 0.11.

Final determination: Rule14 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

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 lists PVS1 as not applicable for this framework.	cspec pvs1_variant_assessment
PS1	N/A	PS1 is intended for a different nucleotide change that produces the same amino acid substitution. The available expert-panel record is for this same c.1799T>G change rather than a separate same-protein comparator.	cspec clinvar
PS2	Not assessed	A published report describes this variant as de novo in a patient with cardiofaciocutaneous syndrome, but the retrieved evidence does not document the parental confirmation details needed to assign PS2 points.	cspec PMID:20735442 clinvar
PS3	Met	In a published functional study, this variant increased ERK and ELK phosphorylation compared with wild type, consistent with an activating effect. Under the BRAF RASopathy specification, one approved functional assay supports PS3 at supporting strength.	PMID:20735442 cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	This variant has been observed in at least one published germline case and in somatic cancer databases, but the retrieved evidence does not provide the RASopathy point total or a case-control enrichment analysis needed to assign PS4.	cspec PMID:20735442 clinvar
PM1	Met	This missense change affects codon 600 within the BRAF CR3 activation segment (amino acids 594-627), a critical functional domain specified by the RASopathy framework. Published structural-functional data also support the importance of the activation segment in BRAF activation.	cspec PMID:15035987
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy PM2 requirement that the variant be absent from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this BRAF RASopathy framework.	cspec
PM4	N/A	This variant is a missense substitution and does not produce an in-frame protein length change or stop-loss effect.	cspec
PM5	Met	Other missense substitutions affecting the same codon have been reported in ClinVar as likely pathogenic or pathogenic, including p.Val600Leu and p.Val600Met. This satisfies the BRAF same-residue comparator rule for PM5 at moderate strength.	cspec clinvar
PM6	Not assessed	A published de novo case was identified, but the retrieved evidence does not provide enough detail to determine whether the report should be scored as assumed de novo under the RASopathy PM6 point system.	cspec PMID:20735442
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec
PP2	Not assessed	This is a missense variant in a gene where missense disease is relevant, but the retrieved evidence did not provide the BRAF missense z score needed to determine whether the >3.09 threshold is met.	cspec
PP3	Met	Computational evidence supports a damaging missense effect. REVEL is 0.925, which is above the RASopathy PP3 threshold of 0.7; BayesDel is 0.357299; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, which is consistent with this being primarily a missense effect rather than a splice-altering variant.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in this BRAF RASopathy framework because phenotype-based case evidence is incorporated into PS4.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the BA1 threshold of at least 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the BS1 threshold of at least 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observations in unaffected individuals were identified, so BS2 cannot be assessed.	cspec
BS3	N/A	BS3 is not applicable in this BRAF RASopathy framework.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	In this RASopathy framework, BP1 is reserved for truncating or loss-of-function variants in genes where gain-of-function missense variants are the established disease mechanism. This variant is missense, so BP1 does not apply.	cspec
BP2	Not assessed	No phase data or alternate molecular explanation in the same gene were identified, so BP2 cannot be assessed.	cspec
BP3	N/A	BP3 is not applicable in this RASopathy framework.	cspec
BP4	Not met	Available computational evidence does not support BP4. REVEL is 0.925, which is above the benign BP4 threshold of 0.3, and BayesDel is 0.357299; although SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, the missense predictor result does not support a benign interpretation.	cspec revel bayesdel spliceai
BP5	Not assessed	No alternate molecular diagnosis or phenotype inconsistency evidence was identified, so BP5 cannot be assessed.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	This is not a synonymous or intronic noncoding variant, so BP7 does not apply.	cspec spliceai

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