Variant classification summary

NM_001354609.1:c.1796C>G

BRAF · NP_001341538.1:p.(Thr599Arg) · NM_001354609.1

GRCh37: chr7:140453139 G>C · GRCh38: chr7:140753339 G>C

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PS3 moderate PM1 moderate PM2 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Thr599Arg)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.1796C>G (p.Thr599Arg) variant has been reported in ClinVar as pathogenic, including an expert panel pathogenic classification, and is also represented in curated cancer variant resources.

2

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

3

In approved functional studies, this variant was classified as pathogenic in both MEK activation and ERK activation assays, supporting abnormal MAPK pathway signaling consistent with the disease mechanism.

4

In silico evidence does not meet the BRAF RASopathy thresholds for PP3 or BP4 because REVEL is 0.359, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is 0.308415.

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, and the BRAF RASopathy specification does not apply PVS1 to this variant type.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No directly reviewed evidence established that this same amino acid change has already been classified as pathogenic from an independent nucleotide change or from an approved analogous RAF position analysis.	cspec vcep_raf_alignment
PS2	Not assessed	No confirmed de novo occurrence with the point threshold required by the BRAF RASopathy specification was directly established from the reviewed evidence.	cspec PMID:19206169 PMID:28650561
PS3	Met	In approved functional studies, this variant was listed as pathogenic in both MEK activation and ERK activation assays, consistent with abnormal downstream MAPK pathway activation. Under the BRAF RASopathy specification, results from 2 different approved assays meet PS3 at Moderate strength.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:19206169
PS4	Not assessed	Affected-case enrichment meeting the RASopathy point threshold was not directly established from the reviewed evidence, so PS4 was not applied.	cspec PMID:19206169 PMID:28650561 clinvar
PM1	Met	Thr599 lies within the BRAF CR3 activation segment (amino acids 594-627), which the BRAF RASopathy specification defines as a critical and well-established functional region for PM1.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the BRAF RASopathy specification, absence from controls supports PM2 at Supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this BRAF RASopathy framework.	cspec
PM4	N/A	This is a missense variant and does not cause a protein length change, so PM4 does not apply.	cspec
PM5	Not assessed	No directly reviewed codon-level evidence established a different pathogenic missense change at this same codon at the strength required by the BRAF RASopathy specification.	cspec
PM6	Not assessed	No assumed or confirmed de novo point total for this variant was directly established from the reviewed evidence, so PM6 was not applied.	cspec PMID:19206169 PMID:28650561
PP1	Not assessed	No segregation data were identified showing this variant cosegregates with disease across the number of informative meioses required for PP1.	cspec
PP2	Not assessed	The BRAF RASopathy specification uses a missense constraint threshold of z score greater than 3.09 for PP2, and that gene-level value was not directly available in the reviewed evidence.	cspec
PP3	Not met	Computational evidence does not meet the BRAF RASopathy threshold for PP3. REVEL is 0.359, which is below the required threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is 0.308415, but this does not change the VCEP missense rule application.	cspec revel spliceai bayesdel
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 Pathogenic.	cspec clinvar
BA1	Not met	This variant does not meet BA1 because it is absent from gnomAD and therefore is below the BRAF RASopathy filtering allele frequency threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant does not meet BS1 because it is absent from gnomAD and therefore is below the BRAF RASopathy filtering allele frequency threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals at the point threshold required for BS2.	cspec
BS3	N/A	BS3 is not applicable in this BRAF RASopathy framework.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 was not applied.	cspec
BP1	N/A	This is a missense variant, whereas the BRAF RASopathy specification limits BP1 to truncating loss-of-function variant types in genes without an established loss-of-function disease mechanism.	cspec
BP2	Not assessed	No phase or co-occurrence evidence meeting the RASopathy point-based BP2 thresholds was identified.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy framework.	cspec
BP4	Not met	Computational evidence does not meet the BRAF RASopathy threshold for BP4. REVEL is 0.359, which is above the benign threshold of 0.3, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is 0.308415, but the VCEP missense rule is not met.	cspec revel spliceai bayesdel
BP5	Not assessed	No alternative molecular explanation data meeting the RASopathy point-based BP5 thresholds were identified.	cspec
BP6	N/A	BP6 is not applicable in this BRAF RASopathy framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 does not apply.	cspec spliceai

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