Variant classification summary

NM_001354609.1:c.739T>G

BRAF · NP_001341538.1:p.(Phe247Val) · NM_001354609.1

GRCh37: chr7:140501333 A>C · GRCh38: chr7:140801533 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.(Phe247Val)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.739T>G (p.Phe247Val) variant has not been observed in COSMIC and has been reported in ClinVar, where the overall classification is likely pathogenic with expert panel review.

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which supports PM2 at supporting strength under the BRAF RASopathy specification.

3

This missense variant lies in BRAF exon 6, a region explicitly designated by the RASopathy VCEP for PM1 application, and other pathogenic or likely pathogenic missense changes have been reported at the same codon 247, supporting PM5 at moderate strength.

4

Computational evidence supports a deleterious missense effect because REVEL is 0.921, above the VCEP PP3 threshold of 0.7, BayesDel is positive at 0.434669, and SpliceAI shows only a possible splice signal with a max delta score of 0.20.

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 case.	cspec pvs1_variant_assessment
PS1	Not met	No evidence was identified that this nucleotide change produces the same amino acid change as a previously established pathogenic variant.	clinvar cspec
PS2	Not assessed	Possible de novo evidence was suggested in submitted records, but no independently verified report with confirmed maternity and paternity and phenotype-specific point scoring was identified here.	clinvar cspec
PS3	Not assessed	No approved variant-specific functional assay result for p.(Phe247Val) was identified from the reviewed materials. Available literature leads and OncoKB citations did not provide sufficient direct evidence to apply PS3.	oncokb vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Not assessed	This variant has been reported in ClinVar, but no deduplicated count of unrelated affected probands or VCEP point total was established from the reviewed evidence, so PS4 could not be applied.	clinvar cspec
PM1	Met	This missense variant lies in BRAF exon 6, which is one of the gene regions explicitly designated by the RASopathy VCEP as eligible for PM1 application.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which meets the BRAF RASopathy VCEP PM2 threshold requiring absence from population controls.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	PM3 is not applicable in this BRAF RASopathy framework.	cspec
PM4	N/A	This is a missense substitution and does not change protein length, so PM4 is not applicable.	cspec
PM5	Met	Other pathogenic or likely pathogenic missense changes have been reported at the same BRAF codon 247 in ClinVar, including p.(Phe247Leu) and p.(Phe247Ser), which supports PM5 at moderate strength under the RASopathy VCEP rule for one pathogenic or likely pathogenic residue change at the same codon.	clinvar cspec
PM6	Not assessed	Possible de novo evidence was suggested, but the reviewed evidence did not establish the level of parental confirmation or independence needed to score PM6.	clinvar cspec
PP1	Not assessed	No segregation data were identified that would allow informative meiosis counting for PP1.	cspec clinvar
PP2	Not assessed	The BRAF RASopathy VCEP allows PP2 for missense variants when the gnomAD missense z score is greater than 3.09, but that gene-level missense constraint value was not retrieved in the reviewed materials.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect: REVEL is 0.921, which is above the RASopathy VCEP PP3 threshold of 0.7, and BayesDel is also positive at 0.434669. SpliceAI shows only a possible splice signal with max delta score 0.20, so PP3 is supported primarily by the missense prediction evidence.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable in this BRAF RASopathy framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it is well below the BA1 threshold of at least 0.05% filtering allele frequency.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the BS1 threshold of at least 0.025% filtering allele frequency.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals at a level that would satisfy the RASopathy VCEP point-based BS2 rule.	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 could not be evaluated.	cspec
BP1	Not met	This criterion is reserved in the RASopathy BRAF framework for truncating loss-of-function variants in the appropriate context, whereas this variant is missense.	cspec
BP2	Not assessed	No evidence was identified for an alternative molecular explanation or phase information that would allow BP2 point scoring.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy framework.	cspec
BP4	Not met	Computational evidence does not support a benign effect because REVEL is 0.921, which is above the BP4 benign threshold of 0.3.	revel cspec
BP5	Not assessed	No evidence was identified for an alternate molecular cause sufficient to assign BP5 points.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or other non-coding variant, so BP7 is not applicable.	cspec

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