Variant classification summary

NM_001354609.1:c.1929A>G

BRAF · NP_001341538.1:p.(Gly643=) · NM_001354609.1

GRCh37: chr7:140449150 T>C · GRCh38: chr7:140749350 T>C

Gene: BRAF Transcript: NM_001354609.1

Final call

Benign

BP4 supporting BP6 supporting benign BS1 strong BA1 stand-alone benign

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Gly643=)

gnomAD AF

0.17825055377921759 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.1929A>G (p.Gly643=) variant is reported in ClinVar as Benign with expert-panel review.

2

This variant is common in population databases, with an allele frequency of 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1, far above the RASopathy VCEP BA1 threshold of 0.05% and BS1 threshold of 0.025%.

3

Computational evidence does not support a damaging effect, with a REVEL score of 0.247 and SpliceAI predicting no significant splice impact with a maximum delta score of 0.01.

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
PM5	N/A	This variant is synonymous and does not create an amino acid substitution, so the RASopathy VCEP same-residue missense PM5 rule does not apply.	cspec pm5_candidates
BP1	N/A	BP1 in this RASopathy specification is reserved for truncating loss-of-function variants in genes in which gain-of-function missense variants are the primary disease mechanism. This variant is synonymous, so BP1 does not apply.	cspec
BP4	Met	Computational evidence supports no meaningful molecular effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the REVEL score is 0.247, which is below the RASopathy VCEP benign threshold of 0.3.	cspec spliceai revel
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 cannot be assigned from the available evidence.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BP2	Not assessed	No phase data or evidence for an alternative molecular explanation in the same gene were identified, so BP2 cannot be assessed from the available information.	cspec
PP2	N/A	PP2 is a missense criterion in this framework. This variant is synonymous, so PP2 does not apply.	cspec
BS3	N/A	BS3 is not used in this VCEP framework.	cspec
PM1	Not met	Available evidence does not support PM1. The RASopathy VCEP restricts PM1 to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627), and p.Gly643= lies outside those specified regions. Cancer Hotspots also did not show this variant in a statistically significant hotspot.	cspec hotspots
PP3	Not met	Computational evidence does not support a deleterious effect. The REVEL score is 0.247, which is below the RASopathy VCEP PP3 threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.	cspec revel spliceai
BP5	Not assessed	No evidence was identified for an alternative molecular explanation in a different gene or for a phenotype fully explained by another cause, so BP5 cannot be assessed from the available information.	cspec
PM3	N/A	PM3 is not applicable in this VCEP framework.	cspec
PP4	N/A	PP4 is not applicable in this VCEP framework because phenotype specificity is handled through other criteria.	cspec
PM4	N/A	PM4 applies to in-frame insertions or deletions and stop-loss variants that change protein length. This synonymous variant does not alter protein length, so PM4 does not apply.	cspec
BS4	Not assessed	No informative family showing lack of segregation was identified for this variant, so BS4 cannot be assigned from the available evidence.	cspec
PM2	Not met	PM2 requires absence from gnomAD, but this variant is common in population databases. In gnomAD v2.1 the allele frequency is 21.18080% (59,743/282,062 alleles), and in gnomAD v4.1 the allele frequency is 17.82506% (287,439/1,612,556 alleles), both far above an absence threshold.	cspec gnomad_v2 gnomad_v4
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BS1	Met	This variant exceeds the RASopathy VCEP BS1 population threshold. The filtering allele frequency threshold is 0.025%, whereas the observed allele frequency is 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1, with many homozygotes in both datasets.	cspec gnomad_v2 gnomad_v4
BP7	Not assessed	This synonymous variant has no predicted splice effect by SpliceAI, which supports one part of BP7, but no conservation evidence was identified to show that the affected nucleotide is not highly conserved. BP7 therefore remains unconfirmed from the available evidence.	cspec spliceai
BS2	Not assessed	The available materials show this variant is very common in population databases, including many homozygotes, but no explicit BS2 point-based healthy-individual assessment under the RASopathy framework was provided. BS2 was therefore not independently assigned in this pass.	cspec gnomad_v2 gnomad_v4
PS1	N/A	PS1 requires the same amino acid change as an established pathogenic variant. This variant is synonymous and does not change the amino acid, so PS1 does not apply.	cspec
BA1	Met	This variant exceeds the RASopathy VCEP BA1 threshold by a large margin. The filtering allele frequency threshold is 0.05%, while the observed allele frequency is 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1; both values are far above the stand-alone benign threshold.	cspec gnomad_v2 gnomad_v4
BP3	N/A	BP3 is not applicable in this VCEP framework.	cspec
PM6	Not assessed	No assumed de novo occurrence without parental confirmation was identified for this variant, so PM6 cannot be assigned from the available evidence.	cspec
PS3	Not met	No approved functional study for this exact variant was identified in the available RASopathy VCEP functional materials, so PS3 cannot be assigned.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.	cspec
PS4	Not met	Available evidence does not support enrichment in affected individuals. No case-control or case-enrichment evidence was identified for this exact variant, and the variant is common in population databases, with allele frequencies of 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1.	cspec gnomad_v2 gnomad_v4 clinvar
PVS1	N/A	PVS1 is not applicable to this variant. It is a synonymous change and does not fall into the null-variant categories used for PVS1 assessment.	cspec pvs1_gene_context pvs1_variant_assessment

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