NM_001354609.1:c.770A>G

BRAF · NP_001341538.1:p.(Gln257Arg) · NM_001354609.1

GRCh37: chr7:140501302 T>C · GRCh38: chr7:140801502 T>C

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PP5 supporting PM1 moderate PP3 supporting PS3 moderate

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Gln257Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.770A>G (p.Gln257Arg) variant has been reported in ClinVar as pathogenic, including expert panel review.

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,613,978 alleles; AF 0.00006%), which is below the BS1 threshold of 0.025% and the BA1 threshold of 0.05%.

In VCEP-approved functional studies, Q257R showed abnormal results in MEK activation, ERK activation, and BRAF kinase activity assays, consistent with a damaging gain-of-function effect.

Computational evidence supports a deleterious missense effect, with REVEL 0.838 above the PP3 threshold of 0.7, a positive BayesDel score of 0.476355, and SpliceAI showing only a low predicted splice effect with a maximum delta score of 0.21.

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
PM5	Not assessed	Available evidence does not establish a different pathogenic or likely pathogenic missense change at codon 257 in BRAF or RAF1, so this codon-based criterion cannot be confirmed from the reviewed evidence.	cspec clinvar
BP1	N/A	This is a missense variant, whereas this criterion is specified here for truncating loss-of-function variants in a gain-of-function disease context.	cspec
BP4	Not met	Computational evidence does not support a benign effect. REVEL is 0.838, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.476355.	cspec revel bayesdel spliceai
PS2	Not assessed	Published reports associated with this variant and cardio-facio-cutaneous syndrome were identified, but the reviewed evidence did not document confirmed maternity and paternity for an exact-variant de novo occurrence, so this criterion cannot be assigned at this time.	cspec clinvar PMID:16439621 PMID:17551924
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BP2	Not assessed	No evidence was identified that this variant occurs with an alternative molecular diagnosis in cis or trans in a way that supports this criterion.	cspec
PP2	Not assessed	This criterion requires a BRAF missense constraint metric above the specified threshold, but the reviewed evidence did not provide the gene-level missense z score needed to confirm the rule.	cspec
BS3	N/A	This expert panel framework does not apply BS3 for this gene specification.	cspec
PM1	Met	This missense variant is located in exon 6, and the RASopathy expert panel explicitly permits PM1 at moderate strength for variants in exon 6 as a critical and well-established functional region.	cspec
PP3	Met	Computational evidence supports a damaging effect. REVEL is 0.838, which is above the PP3 threshold of 0.7, BayesDel is positive at 0.476355, and SpliceAI shows only a low predicted splice effect with a maximum delta score of 0.21, supporting interpretation primarily as a deleterious missense change.	cspec revel bayesdel spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was identified in the reviewed evidence.	cspec
PM3	N/A	This criterion is for recessive disorders and is not applicable in this framework.	cspec
PP4	N/A	This expert panel framework does not apply PP4 for this condition because phenotype specificity is addressed through PS4-based specifications.	cspec
PM4	N/A	This is a missense substitution and does not change protein length, so this criterion for in-frame length changes or stop-loss variants does not apply.	cspec
BS4	Not assessed	No family data showing lack of segregation were identified for this variant.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 1/1,613,978 alleles (AF 6.195871319187746e-07; 0.00006%), so it is not absent from controls and does not meet this VCEP PM2 rule.	cspec gnomad_v2 gnomad_v4
BP6	N/A	This criterion is not used by this expert panel framework.	cspec
BS1	Not met	Population frequency is far below the BS1 threshold. The highest observed frequency is 0.00008% in the European non-Finnish population, which is below the BS1 threshold of 0.025%.	cspec gnomad_v4
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so this criterion does not apply.	cspec
BS2	Not assessed	No evidence was identified that this variant is observed in healthy individuals in a manner that satisfies the RASopathy point-based BS2 specification.	cspec gnomad_v4
PS1	Not assessed	The reviewed evidence did not establish a previously classified pathogenic variant producing the same amino acid change through a different nucleotide change, so this criterion cannot be confirmed from the current record.	cspec clinvar
BA1	Not met	Population frequency is well below the BA1 threshold. The highest observed frequency is 0.00008%, which is below the BA1 threshold of 0.05%.	cspec gnomad_v4
BP3	N/A	This criterion is not applicable in this expert panel framework.	cspec
PM6	Not assessed	Published reports suggest this variant has been observed in affected individuals, but the reviewed evidence did not provide sufficient patient-level documentation to score an assumed de novo occurrence under the RASopathy point framework.	cspec clinvar PMID:16439621 PMID:17551924
PS3	Met	VCEP-approved functional studies show abnormal effects in more than one approved assay for this variant. Q257R is listed as pathogenic in MEK activation, ERK activation, and BRAF kinase activity assays, supporting a damaging gain-of-function effect.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PP1	Not assessed	No informative meioses showing segregation with disease were identified for this variant.	cspec
PS4	Not assessed	This variant has been reported in affected individuals and is classified as pathogenic in ClinVar, but the reviewed evidence did not establish the exact number of independent affected probands needed to score the RASopathy PS4 point framework.	cspec clinvar PMID:16439621 PMID:16474404 PMID:17551924
PVS1	N/A	This variant is a missense substitution and does not fall within the null-variant categories used for PVS1 assessment.	cspec pvs1_gene_context pvs1_variant_assessment

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