NM_001354609.1:c.739T>C

BRAF · NP_001341538.1:p.(Phe247Leu) · NM_001354609.1

GRCh37: chr7:140501333 A>G · GRCh38: chr7:140801533 A>G

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PM1 moderate PM2 supporting PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Phe247Leu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.739T>C (p.Phe247Leu) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including by the ClinGen RASopathy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, consistent with the BRAF RASopathy PM2_Supporting requirement for absence from population controls.

This missense change lies in BRAF exon 6, a region specifically designated by the BRAF RASopathy specification as eligible for PM1.

Computational evidence supports a deleterious effect, with REVEL 0.902 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.278133, and SpliceAI showing no meaningful splice impact with a maximum delta score of 0.10.

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, not a predicted null variant, and the BRAF RASopathy framework marks PVS1 as not applicable for this case.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No verified evidence was identified showing the same amino acid change from a different nucleotide substitution, or an established analogous RAF1/BRAF residue match that satisfies the BRAF RASopathy PS1 rule.	cspec vcep_raf_alignment
PS2	Not assessed	Published evidence suggesting possible de novo occurrence was flagged for follow-up, but no directly verified proband-level parental testing details were available to assign de novo points under the BRAF RASopathy framework.	cspec PMID:20301303 PMID:20301365 PMID:20876176 PMID:25173338
PS3	Not assessed	Review of the RASopathy VCEP approved functional study materials did not confirm this exact variant in a qualifying approved assay, so pathogenic functional evidence was not applied.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb PMID:28512244 PMID:29533785 PMID:31515458
PS4	Not assessed	The variant is reported in ClinVar, but a deduplicated count of unrelated affected individuals and the corresponding RASopathy point total were not directly verified from the available materials, so PS4 was not assigned.	clinvar cspec PMID:20301303 PMID:20301365 PMID:20876176 PMID:25173338
PM1	Met	This missense variant is in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical, well-established region eligible for PM1.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 requirement of absence from population controls.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not used in the BRAF RASopathy framework for this autosomal dominant disorder context.	cspec
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 does not apply.	cspec
PM5	Not assessed	The BRAF framework uses classic same-residue PM5 logic, but no verified qualifying pathogenic or likely pathogenic missense comparator at codon 247 was confirmed from the available materials.	cspec pm5_candidates
PM6	Not assessed	Possible de novo literature sources were identified, but no directly verified report was available to determine whether reduced de novo points should be assigned under PM6.	cspec PMID:20301303 PMID:20876176
PP1	Not assessed	No segregation data were identified showing this variant co-segregating with disease in informative meioses.	cspec PMID:25173338
PP2	Met	This is a missense variant in BRAF, a gene with missense-mediated RASopathy disease, and the gene-level gnomAD missense z score is 3.72, which is above the BRAF RASopathy PP2 threshold of 3.09.	cspec gnomad_v4
PP3	Met	Computational evidence supports a deleterious missense effect: REVEL is 0.902, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10. BayesDel is also positive at 0.278133.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not used in the BRAF RASopathy framework because phenotype-based case evidence is incorporated through 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 v4.1 and therefore is below the BRAF RASopathy BA1 threshold of 0.05% filtering allele frequency.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore is below the BRAF RASopathy BS1 threshold of 0.025% filtering allele frequency.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals sufficient to assign benign observation points.	cspec
BS3	N/A	BS3 is not applicable in the BRAF RASopathy framework for this case.	cspec
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant in an informative family.	cspec PMID:25173338
BP1	N/A	BP1 in the BRAF RASopathy framework is reserved for truncating loss-of-function variants in a gain-of-function disease setting, and this variant is missense.	cspec
BP2	Not assessed	No co-occurrence or phase data were identified showing this variant with an alternative molecular cause of disease in the same gene.	cspec PMID:20301303
BP3	N/A	BP3 is not applicable in the BRAF RASopathy framework.	cspec
BP4	Not met	Although SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10, the missense REVEL score is 0.902, which is well above the BRAF RASopathy BP4 threshold of 0.3, so benign computational evidence is not supported.	cspec revel spliceai
BP5	Not assessed	No alternative molecular explanation for the phenotype was identified that would support benign points under BP5.	cspec
BP6	N/A	BP6 is not used in this VCEP framework, so outside benign assertions were not counted as independent evidence.	cspec
BP7	N/A	This is not a synonymous, intronic, or other non-coding variant, so BP7 does not apply.	cspec spliceai

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