NM_001354609.1:c.741T>G

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

GRCh37: chr7:140501331 A>C · GRCh38: chr7:140801531 A>C

Gene: BRAF Transcript: NM_001354609.1

Final call

Likely Pathogenic

PM1 moderate PM2 supporting PM5 moderate PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Phe247Leu)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.741T>G (p.Phe247Leu) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with an expert-panel Pathogenic classification.

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

Within the BRAF RASopathy framework, this missense change lies in exon 6, a specified critical functional domain, and other expert-panel reviewed missense substitutions at the same codon, p.Phe247Val and p.Phe247Ser, have been classified as likely pathogenic.

Computational evidence supports a deleterious missense effect, with REVEL 0.816 exceeding the PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08.

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 marks PVS1 as not applicable for this gene framework.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant producing the same amino acid change, p.(Phe247Leu), by a different nucleotide change was identified in the reviewed sources, so PS1 is not met.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with confirmed maternity and paternity was identified in the reviewed evidence, so PS2 cannot be applied at this time.	cspec
PS3	Not assessed	Approved functional assay frameworks were identified for BRAF, but no directly reviewed variant-specific assay result for p.(Phe247Leu) was available here, so PS3 was not applied.	cspec oncokb vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:28512244 PMID:29533785 PMID:31515458
PS4	Not assessed	The variant is classified by an expert panel in ClinVar, but the reviewed evidence did not provide the case counts or point-based affected-individual data needed to score PS4 within the BRAF RASopathy framework.	cspec clinvar
PM1	Met	This missense variant is located in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical and well-established functional domain for PM1 application.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 threshold of absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this BRAF RASopathy framework.	cspec
PM4	N/A	This is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 is not applicable to this missense change.	cspec
PM5	Met	Other missense changes at the same codon have been reported in ClinVar with expert-panel review, including p.(Phe247Val) and p.(Phe247Ser), both classified as likely pathogenic. This supports PM5 at moderate strength for a different missense change at the same residue.	cspec clinvar
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified in the reviewed evidence, so PM6 was not applied.	cspec
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 BRAF, but the reviewed evidence did not provide the gene-level missense constraint value needed to determine whether the missense z score exceeds the BRAF RASopathy PP2 threshold.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect. REVEL is 0.816, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, supporting a protein-level rather than splice-driven effect.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in this BRAF RASopathy framework because phenotype-based weighting 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, so it does not meet the BA1 population threshold of filtering allele frequency at or above 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1, so it does not meet the BS1 population threshold of filtering allele frequency at or above 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals in numbers sufficient for BS2 scoring.	cspec
BS3	N/A	BS3 is not applicable in this BRAF RASopathy framework.	cspec
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	This criterion is reserved in the BRAF RASopathy framework for truncating variants in genes where gain-of-function missense variants are the relevant disease mechanism. It does not apply to this missense variant.	cspec
BP2	Not assessed	No evidence was identified for an alternative molecular explanation in cis or trans that would support BP2 scoring.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy framework.	cspec
BP4	Not met	Available computational evidence does not support BP4 for a benign missense effect. REVEL is 0.816, which is above the benign threshold of 0.3, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.08.	cspec revel spliceai bayesdel
BP5	Not assessed	No evidence was identified for a fully explanatory alternative molecular diagnosis or a phenotype inconsistent with a RASopathy that would support BP5 scoring.	cspec
BP6	N/A	BP6 is not used in this expert-panel framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 does not apply.	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.