Variant classification summary

NM_001354609.1:c.1383A>G

BRAF · NP_001341538.1:p.(Gln461=) · NM_001354609.1

GRCh37: chr7:140481425 T>C · GRCh38: chr7:140781625 T>C

Gene: BRAF Transcript: NM_001354609.1

Final call

Benign

BA1 stand-alone benign BP4 supporting BP6 supporting benign

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Gln461=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.1383A>G (p.Gln461=, p.Q461=) variant has been reported in ClinVar as benign, including a benign expert-panel assertion from the ClinGen RASopathy Variant Curation Expert Panel, and it has not been established as a statistically significant hotspot at codon 461.

2

This variant is present in gnomAD v2.1 at 0.12339% overall (349/282834 alleles; 3 homozygotes), with an African/African American frequency of 1.30146% and grpmax filtering allele frequency of 1.2192%, which is above the BRAF RASopathy BA1 threshold of 0.05%.

3

Computational data do not suggest a harmful effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084.

Final determination: Rule17 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 Benign.

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 synonymous variant does not fall into the null-variant categories used for PVS1, and the generic PVS1 assessment did not support PVS1 application.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires a previously established pathogenic amino acid substitution, but this variant is synonymous and does not change the encoded amino acid.	cspec
PS2	Not assessed	No confirmed de novo observation with parental testing and phenotype-based point scoring was identified for this variant.	cspec
PS3	Not assessed	No approved functional study for this exact variant was identified in the reviewed RASopathy VCEP functional materials.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	No affected-individual enrichment or point-based case evidence was identified to support PS4 for this variant.	cspec clinvar
PM1	Not met	Although codon 461 falls within the BRAF P-loop region listed by the RASopathy VCEP, this variant is synonymous and Cancer Hotspots did not establish Q461 as a statistically significant hotspot, so PM1 is not applied.	cspec hotspots
PM2	Not met	This variant is present in gnomAD and therefore is not absent from controls, so PM2 is not met.	gnomad_v2 cspec
PM3	N/A	PM3 is not applicable in this RASopathy framework.	cspec
PM4	N/A	PM4 applies to in-frame insertions/deletions or stop-loss variants, and this variant is a synonymous substitution.	cspec
PM5	N/A	The RASopathy VCEP uses classic same-residue missense PM5 logic, but this variant is not missense-like, so PM5 is not applicable.	cspec pm5_candidates
PM6	Not assessed	No presumed de novo observation without full parental confirmation was identified for this variant.	cspec
PP1	Not assessed	No segregation data were identified for this variant.	cspec
PP2	N/A	PP2 is a missense criterion, and this variant is synonymous.	cspec
PP3	Not met	Computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084, which is below the PP3 threshold of 0.7.	spliceai revel cspec
PP4	N/A	PP4 is not applicable in this RASopathy framework.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Met	This variant exceeds the BRAF RASopathy BA1 population threshold. In gnomAD v2.1, the overall allele frequency is 0.12339% (349/282834 alleles) and the grpmax filtering allele frequency is 1.2192%, both above the BA1 threshold of 0.05%.	gnomad_v2 cspec
BS1	Not assessed	The observed population frequency also exceeds the BS1 threshold, but BA1 is already met and BS1 is not additionally applied to avoid double counting the same population evidence.	gnomad_v2 cspec
BS2	Not assessed	Population data show 3 homozygotes in gnomAD, but BS2 in this framework requires phenotype-aware unaffected observations, which were not identified for this variant.	gnomad_v2 cspec
BS3	N/A	BS3 is not applicable in this RASopathy framework.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant.	cspec
BP1	N/A	BP1 in this framework is used for truncating loss-of-function variants in genes with primarily gain-of-function disease mechanism, and this variant is not truncating.	cspec
BP2	Not assessed	No phase data or alternative molecular explanation in the same gene were identified for this variant.	cspec
BP3	N/A	BP3 is not applicable in this RASopathy framework.	cspec
BP4	Met	Computational evidence does not suggest a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084, which is below the BP4 threshold of 0.3.	spliceai revel cspec
BP5	Not assessed	No alternative molecular diagnosis in another gene or fully explanatory non-RASopathy diagnosis was identified for this variant.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	Not assessed	This is a synonymous variant and SpliceAI predicts no significant splice impact, but no conservation evidence was identified to confirm the full BP7 requirement that the affected nucleotide is not highly conserved.	spliceai cspec

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.