Variant classification summary

NM_001354609.1:c.483G>C

BRAF · NP_001341538.1:p.(Leu161=) · NM_001354609.1

GRCh37: chr7:140534430 C>G · GRCh38: chr7:140834630 C>G

Gene: BRAF Transcript: NM_001354609.1

Final call

Likely Benign

BS1 strong BP4 supporting BP6 supporting benign

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Leu161=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.483G>C (p.Leu161=) variant has not been identified as a statistically significant hotspot in Cancer Hotspots and has been reported in ClinVar as benign/likely benign, including a likely benign expert-panel classification.

2

This variant is present in gnomAD, with grpmax filtering allele frequency 0.03792% in v2.1 and 0.04133% in v4.1, which is above the BRAF VCEP BS1 threshold of 0.025% but below the BA1 threshold of 0.05%.

3

In silico splice prediction does not support a deleterious effect, with SpliceAI showing a maximum delta score of 0.02 for this synonymous change.

Final determination: Rule18 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 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 variant is a synonymous substitution, and the BRAF RASopathy VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also indicates that this variant is not a nonsense, frameshift, or canonical +/-1,2 splice-site variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This variant does not change the encoded amino acid and therefore does not meet the PS1 requirement for the same pathogenic amino acid change as a previously established pathogenic variant.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.	cspec
PS3	Not assessed	No approved functional study for this specific variant was identified to show a damaging effect on protein function or splicing.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	No affected-proband series or case-control enrichment data were identified for this variant.	cspec clinvar
PM1	Not met	This variant is in exon 3 at p.Leu161=, which is outside the BRAF VCEP-listed PM1 regions (exon 6, exon 11, P-loop amino acids 459-474, and CR3 activation segment amino acids 594-627). Cancer Hotspots also did not identify this site as a statistically significant hotspot.	cspec hotspots
PM2	Not met	This variant is present in population databases and therefore is not absent from controls. In gnomAD v2.1 the total allele frequency is 0.00566% with grpmax FAF 0.03792%, and in gnomAD v4.1 the total allele frequency is 0.00297% with grpmax FAF 0.04133%.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this BRAF RASopathy framework.	cspec
PM4	N/A	This variant is a single-nucleotide synonymous substitution and does not cause an in-frame protein length change or stop-loss event.	cspec
PM5	N/A	This variant does not alter the amino acid sequence, so the PM5 missense-at-same-codon rule does not apply.	cspec
PM6	Not assessed	No presumed de novo occurrence with incomplete 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	Available computational evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, which is below a level that would support PP3.	cspec spliceai
PP4	N/A	PP4 is not applicable in this BRAF RASopathy framework.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	The BRAF VCEP BA1 threshold is gnomAD filtering allele frequency >=0.05%. This variant has grpmax FAF 0.03792% in gnomAD v2.1 and 0.04133% in gnomAD v4.1, both below the BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Met	The BRAF VCEP BS1 threshold is gnomAD filtering allele frequency >=0.025%. This variant exceeds that threshold in both population datasets, with grpmax FAF 0.03792% in gnomAD v2.1 and 0.04133% in gnomAD v4.1.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in well-phenotyped unaffected individuals sufficient for BS2 scoring.	cspec gnomad_v2 gnomad_v4
BS3	N/A	BS3 is not applicable in this BRAF RASopathy framework.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant.	cspec
BP1	N/A	BP1 in this framework applies to truncating loss-of-function variants in a gain-of-function disease setting, and this variant is not a truncating variant.	cspec
BP2	Not assessed	No evidence was identified that this variant occurs with an alternative molecular explanation in cis or trans sufficient for BP2 scoring.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy framework.	cspec
BP4	Met	Available computational evidence supports no functional impact on splicing. SpliceAI predicts no significant splice effect for this synonymous variant, with a maximum delta score of 0.02.	cspec spliceai
BP5	Not assessed	No evidence was identified for an alternative molecular cause of disease sufficient for BP5 scoring.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Not assessed	This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but no nucleotide conservation evidence was identified to satisfy the full BP7 rule.	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.