NM_001354609.1:c.1787G>T

BRAF · NP_001341538.1:p.(Gly596Val) · NM_001354609.1

GRCh37: chr7:140453148 C>A · GRCh38: chr7:140753348 C>A

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Gly596Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.1787G>T (p.Gly596Val) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic with expert-panel review.

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

In a published functional study, BRAF p.Gly596Val caused abnormal zebrafish developmental phenotypes and showed downstream ERK activation, consistent with dysregulated MAPK signaling.

Computational evidence supports a deleterious missense effect, with REVEL 0.989 above the BRAF PP3 threshold of 0.7, BayesDel 0.588239, and SpliceAI predicting no significant splice effect with a maximal delta score of 0.07.

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 null variant, and the BRAF RASopathy specification lists PVS1 as not applicable for this variant type.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No different nucleotide change producing the same amino acid substitution, p.(Gly596Val), was identified from the reviewed evidence, so PS1 is not met.	clinvar cspec
PS2	Not assessed	Published disease association is strong, but no directly reviewed case-level evidence in the available materials confirmed a de novo occurrence with sufficient parentage documentation to score PS2 points.	cspec clinvar PMID:16439621
PS3	Met	In a published functional study, expression of BRAF p.(Gly596Val) in zebrafish caused abnormal embryonic elongation and developmental abnormalities, and phospho-ERK assays showed downstream ERK activation, consistent with dysregulated MAPK signaling. These data support an abnormal functional effect consistent with the disease mechanism and support PS3 at Supporting strength.	PMID:19376813 vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Not assessed	This variant has been reported in ClinVar and has been observed in somatic cancer databases, but the available materials do not provide the unrelated germline proband counts or point-based case evidence needed to apply the BRAF RASopathy PS4 rule.	clinvar oncokb cspec
PM1	Met	This missense variant affects Gly596, which lies within the BRAF CR3 activation segment (amino acids 594-627), a critical and well-established functional domain specifically listed for PM1 in the BRAF RASopathy specification. This meets PM1 at Moderate strength.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the BRAF RASopathy specification, absence from gnomAD meets PM2 at Supporting strength.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable under the BRAF RASopathy specification.	cspec
PM4	N/A	This is a missense substitution without a protein length change, so PM4 is not applicable.	cspec
PM5	Not met	A different missense change at the same codon, p.(Gly596Cys), was identified in ClinVar, but it has conflicting classifications of pathogenicity rather than an established pathogenic or likely pathogenic classification. Therefore the BRAF same-codon PM5 rule is not met from the reviewed evidence.	clinvar cspec vcep_raf_alignment
PM6	Not assessed	No directly reviewed case-level evidence showed this variant as assumed de novo with the documentation needed to assign PM6 points.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec
PP2	Not assessed	The BRAF RASopathy specification allows PP2 when the missense constraint z score is greater than 3.09, but no directly reviewed gene-level missense z score was identified in the available materials for this adjudication.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect. REVEL is 0.989, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.588239, and SpliceAI predicts no significant splice impact with a maximal delta score of 0.07. For this missense variant, the available computational evidence supports PP3 at Supporting strength.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable under the BRAF RASopathy specification.	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 and does not reach the BRAF RASopathy BA1 threshold of at least 0.05% filtering allele frequency.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD and does not reach the BRAF RASopathy 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 in a quantity sufficient to assign BS2 points.	cspec
BS3	N/A	BS3 is not applicable under the BRAF RASopathy specification.	cspec
BS4	Not assessed	No non-segregation evidence was identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	This is not a truncating variant, so the BRAF RASopathy BP1 truncating-variant rule is not applicable.	cspec
BP2	Not assessed	No phase data or point-based evidence were identified to support BP2.	cspec
BP3	N/A	BP3 is not applicable under the BRAF RASopathy specification.	cspec
BP4	Not met	Available computational evidence does not support a benign effect. REVEL is 0.989, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.588239. SpliceAI predicts no significant splice impact with a maximal delta score of 0.07, but this does not overcome the strongly deleterious missense prediction profile.	revel bayesdel spliceai cspec
BP5	Not assessed	No evidence was identified for an alternate molecular explanation with point-based support to apply BP5.	cspec
BP6	N/A	BP6 is not applicable under the BRAF RASopathy specification.	cspec
BP7	N/A	This is a missense variant rather than a synonymous or eligible intronic variant, so BP7 is not applicable.	cspec

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