Variant classification summary

NM_001354609.1:c.793G>C

BRAF · NP_001341538.1:p.(Gly265Arg) · NM_001354609.1

GRCh37: chr7:140501279 C>G · GRCh38: chr7:140801479 C>G

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PM1 moderate PM2 supporting PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Gly265Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.793G>C (p.Gly265Arg) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with an expert panel likely pathogenic classification and additional pathogenic or likely pathogenic clinical laboratory submissions.

2

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

3

Computational evidence supports a damaging missense effect, with REVEL 0.917 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.403109 in a deleterious direction, and SpliceAI showing no significant predicted splice impact (maximum delta score 0.00).

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 marks PVS1 as not applicable. The generic PVS1 assessment also indicates that this variant does not fall into a nonsense, frameshift, or canonical +/-1,2 splice category.	cspec pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternate nucleotide change producing the same amino acid substitution was identified, so available evidence does not support PS1 for this variant.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with sufficient case-level phenotypic detail and parental confirmation was identified, so PS2 cannot be applied from the available evidence.	cspec clinvar
PS3	Not assessed	Approved BRAF functional assay frameworks are available, but no variant-specific result for p.(Gly265Arg) was identified in the retrieved materials. Available evidence therefore does not support PS3 at this time.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	This variant is reported in ClinVar and has been observed once in COSMIC, but no case-count or case-control evidence meeting the RASopathy point-based PS4 framework was identified. PS4 is therefore not applied.	cspec clinvar hotspots
PM1	Met	This missense variant affects p.(Gly265Arg) in BRAF exon 6. The BRAF RASopathy specification explicitly recognizes exon 6 as a PM1 region, so PM1 is met at moderate strength even though this variant was not identified as a statistically significant cancer hotspot.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 threshold requiring absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the BRAF RASopathy framework.	cspec
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 does not apply.	cspec
PM5	Not met	No different pathogenic or likely pathogenic missense change at codon 265 was identified from the available evidence, so PM5 is not met.	cspec clinvar
PM6	Not assessed	No probable de novo observation with enough evidence for point assignment was identified, so PM6 cannot be applied from the available evidence.	cspec clinvar
PP1	Not assessed	No segregation data or informative meiosis count was identified for this variant, so PP1 cannot be applied.	cspec clinvar
PP2	Met	This is a missense variant in BRAF, and the observed missense constraint z score is 3.99, which is above the BRAF RASopathy PP2 threshold of 3.09. This supports PP2 at supporting strength.	cspec
PP3	Met	Computational evidence supports a damaging missense effect. REVEL is 0.917, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.403109 in a deleterious direction, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting interpretation as a missense rather than splicing effect.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in the BRAF RASopathy framework because phenotype specificity is handled through other criteria such as PS4 and the de novo point-based 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 its observed population frequency is 0%, which is below the BA1 threshold of 0.05%. BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the BS1 threshold of 0.025%. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in unaffected individuals at a level meeting the RASopathy BS2 point framework, so BS2 cannot be applied.	cspec
BS3	N/A	BS3 is not applicable in the BRAF RASopathy framework.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	No lack-of-segregation evidence in an informative family was identified, so BS4 cannot be applied.	cspec clinvar
BP1	N/A	BP1 in this framework is used for truncating variants in a gain-of-function RASopathy gene without an established loss-of-function disease mechanism. This variant is missense, so BP1 does not apply.	cspec
BP2	Not assessed	No evidence was identified for an alternative molecular explanation in cis or trans meeting the RASopathy BP2 point framework, so BP2 cannot be applied.	cspec
BP3	N/A	BP3 is not applicable in the BRAF RASopathy framework.	cspec
BP4	Not met	Available computational evidence does not support BP4. REVEL is 0.917, which is above the benign BP4 threshold of 0.3, and BayesDel is also in a deleterious direction. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, that does not override the missense prediction profile.	cspec revel bayesdel spliceai
BP5	Not assessed	No evidence was identified for a fully explanatory alternative molecular diagnosis or a phenotype inconsistency meeting the RASopathy BP5 point framework, so BP5 cannot be applied.	cspec
BP6	N/A	BP6 is not for use in this VCEP framework.	cspec
BP7	N/A	This is a missense variant, not a synonymous or qualifying intronic variant, so BP7 does not apply.	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.