Variant classification summary

NM_001354609.1:c.730A>C

BRAF · NP_001341538.1:p.(Thr244Pro) · NM_001354609.1

GRCh37: chr7:140501342 T>G · GRCh38: chr7:140801542 T>G

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Thr244Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.730A>C (p.Thr244Pro) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including an expert panel Pathogenic classification.

2

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

3

This missense change affects BRAF exon 6, a region specified by the RASopathy VCEP for PM1, and computational evidence supports a deleterious missense effect with REVEL 0.855, BayesDel 0.418359, and no major predicted splice effect by SpliceAI (maximum delta score 0.09).

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 variant is a missense substitution, and the BRAF RASopathy VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also does not apply because this variant is not a nonsense, frameshift, or canonical splice-site variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified that this variant produces the same amino acid change as a previously established pathogenic variant through a different nucleotide change, including the analogous BRAF/RAF1 provision in the RASopathy VCEP rules.	cspec
PS2	Not assessed	Published germline reports are linked for this variant, but the retrieved evidence does not provide case-level confirmation of de novo occurrence with confirmed maternity and paternity required for PS2 point assignment.	cspec clinvar PMID:17551924 PMID:19206169 PMID:19416762
PS3	Not assessed	The RASopathy VCEP-approved functional study materials were reviewed, but no variant-specific approved assay result for p.(Thr244Pro) was identified in the retrieved evidence to support PS3 assignment.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:18413255 PMID:22142829 PMID:24033266
PS4	Not assessed	This variant has been reported in ClinVar, including an expert panel Pathogenic classification, but the retrieved evidence does not provide the independent affected-case counts or point total required for RASopathy VCEP PS4 scoring.	cspec clinvar PMID:17551924 PMID:18042262 PMID:18413255 PMID:19206169 PMID:19416762 PMID:22142829 PMID:24033266 PMID:27521173
PM1	Met	This missense variant affects BRAF exon 6, which is a critical and well-established region specifically listed by the RASopathy VCEP for PM1 application.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the RASopathy VCEP PM2 threshold requiring absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable because the BRAF RASopathy framework is not using a recessive trans-with-pathogenic-variant model for this condition.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution and does not change protein length through an in-frame insertion, in-frame deletion, or stop-loss event.	cspec
PM5	Not assessed	No different pathogenic or likely pathogenic missense change at codon 244 was identified in the retrieved evidence, so PM5 could not be assigned from the materials reviewed.	cspec clinvar
PM6	Not assessed	Published germline reports are linked for this variant, but the retrieved evidence does not document an assumed or confirmed de novo occurrence with enough case-level detail to assign PM6 points.	cspec clinvar PMID:17551924 PMID:19206169 PMID:19416762
PP1	Not assessed	No segregation data were identified showing this variant co-segregates with a RASopathy phenotype across informative meioses.	cspec
PP2	Not assessed	This is a missense variant in a gene where missense variation is clinically relevant, but the retrieved evidence does not provide the gnomAD missense z score needed for the BRAF RASopathy VCEP PP2 threshold (>3.09).	cspec
PP3	Met	Computational evidence supports a deleterious missense effect. REVEL is 0.855, which is above the RASopathy VCEP PP3 threshold of 0.7; BayesDel is also positive at 0.418359. SpliceAI predicts no major splice effect with a maximum delta score of 0.09, so the computational signal is consistent with a missense rather than splice mechanism.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in this RASopathy VCEP framework because phenotype-specific evidence is handled through PS4 rather than PP4.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is well below the BA1 threshold of 0.05% filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of 0.025% filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified that this variant is present in unaffected individuals at a level that would contribute benign evidence under the RASopathy point-based framework.
BS3	N/A	BS3 is not applicable in this BRAF RASopathy VCEP framework.	cspec
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with disease.	cspec
BP1	N/A	This criterion is reserved in the RASopathy framework for truncating or other loss-of-function variants in genes where gain-of-function missense variation is the relevant disease mechanism. This variant is a missense substitution, so BP1 does not apply.	cspec
BP2	Not assessed	No evidence was identified that this variant occurs with another pathogenic RASopathy variant in a configuration that would support BP2 points.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy VCEP framework.	cspec
BP4	Not met	Benign computational evidence is not supported. REVEL is 0.855, which is above the BP4 benign threshold of 0.3 for missense variants. Although SpliceAI predicts no major splice effect with a maximum delta score of 0.09, the missense prediction does not support a benign interpretation.	cspec revel spliceai
BP5	Not assessed	No alternative molecular diagnosis or non-RASopathy explanation was identified that would support BP5 points.	cspec
BP6	N/A	BP6 is not applicable because this criterion is not used by the ClinGen Sequence Variant Interpretation VCEP Review Committee in the BRAF RASopathy framework.	cspec
BP7	N/A	BP7 does not apply because this variant is not synonymous or intronic; it is a missense substitution.	cspec

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