Variant classification summary

NM_001354609.1:c.708C>T

BRAF · NP_001341538.1:p.(Asn236=) · NM_001354609.1

GRCh37: chr7:140507763 G>A · GRCh38: chr7:140807963 G>A

Gene: BRAF Transcript: NM_001354609.1

Final call

Benign

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

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Asn236=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.708C>T (p.Asn236=) variant has been reported in ClinVar as benign, including a benign expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is present in population databases above the BRAF RASopathy VCEP BA1 threshold of 0.05%, with a grpmax filtering allele frequency of 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1; the highest observed population frequency is in South Asian individuals at 0.17678% in gnomAD v2.1 and 0.14861% in gnomAD v4.1.

3

This is a synonymous variant, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, supporting no meaningful impact on splicing.

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 is a synonymous variant, not a nonsense, frameshift, or canonical +/-1 or 2 splice variant, so PVS1 does not apply.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This variant does not change the amino acid sequence, so the same-amino-acid pathogenic-variant rule does not apply.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence.	cspec clinvar
PS3	Not assessed	No approved functional study for this exact variant was identified, so PS3 cannot be applied.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	No case-enrichment or point-based affected-individual evidence was identified for this variant, and the variant is not absent from population databases, so PS4 cannot be applied.	cspec clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant is in exon 5 at codon 236, which is outside the BRAF RASopathy VCEP PM1 regions limited to exon 6, exon 11, the P-loop (amino acids 459-474), and the CR3 activation segment (amino acids 594-627).	cspec hotspots
PM2	Not met	This variant is present in gnomAD, so it does not meet the PM2 requirement for absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this RASopathy BRAF framework.	cspec
PM4	N/A	This is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 does not apply.	cspec
PM5	N/A	This variant does not create a novel missense change at codon 236, so PM5 does not apply.	cspec
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 cannot be applied from the available evidence.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec clinvar
PP2	N/A	PP2 is a missense-based rule, and this variant is synonymous.	cspec
PP3	Not met	Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, and no applicable missense predictor result was identified for this synonymous variant.	cspec spliceai
PP4	N/A	PP4 is not applicable in this RASopathy BRAF framework.	cspec
PP5	N/A	PP5 is not used in this framework.	cspec
BA1	Met	Population frequency exceeds the RASopathy VCEP BA1 threshold of 0.05%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.05% threshold.	cspec gnomad_v2 gnomad_v4
BS1	Met	Population frequency exceeds the RASopathy VCEP BS1 threshold of 0.025%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.025% threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Population observations were identified, including rare homozygotes in gnomAD, but no phenotype-confirmed unaffected-case evidence was identified to score BS2 under the RASopathy VCEP point system.	cspec gnomad_v2 gnomad_v4
BS3	N/A	BS3 is not applicable in this RASopathy BRAF framework.	cspec
BS4	Not assessed	No informative non-segregation data were identified for this variant, so BS4 cannot be applied.	cspec clinvar
BP1	N/A	BP1 in this RASopathy framework is for truncating loss-of-function variants in genes without an established loss-of-function disease correlation, and this variant is a synonymous substitution.	cspec
BP2	Not assessed	No evidence of an alternative molecular cause in the same gene or phasing information relevant to BP2 was identified.	cspec
BP3	N/A	BP3 is not applicable in this RASopathy BRAF framework.	cspec
BP4	Met	Computational evidence supports no meaningful effect. This synonymous variant has no applicable REVEL score, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, which is consistent with negligible splicing effect.	cspec spliceai
BP5	Not assessed	No alternative molecular diagnosis in a different gene or phenotype explanation relevant to BP5 was identified.	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 with a maximum delta score of 0.06, but the available evidence reviewed here did not establish whether the altered nucleotide is not highly conserved, so BP7 was not fully assessed.	cspec spliceai

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