NM_001354609.1:c.722C>A

BRAF · NP_001341538.1:p.(Thr241Lys) · NM_001354609.1

GRCh37: chr7:140501350 G>T · GRCh38: chr7:140801550 G>T

Gene: BRAF Transcript: NM_001354609.1

Final call

Likely Pathogenic

PM1 moderate PM2 supporting PM5 moderate PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Thr241Lys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.722C>A (p.Thr241Lys) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in reference populations.

A different missense change at the same residue, p.Thr241Pro, is listed as pathogenic/likely pathogenic in the RASopathy VCEP approved functional-study materials, supporting same-residue evidence under the BRAF specification.

Computational evidence supports a deleterious missense effect because REVEL is 0.946, above the BRAF PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.

Final determination: Rule14 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 Likely Pathogenic.

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 does not fall into the null-variant categories used for PVS1; the BRAF RASopathy specification also marks PVS1 as not applicable for this case.	cspec pvs1_variant_assessment
PS1	Not met	No evidence was identified that a different nucleotide change produces the same p.(Thr241Lys) amino acid substitution with an established pathogenic classification.	cspec
PS2	Not assessed	No parentage-confirmed de novo report for this exact variant was identified from the available evidence, so the point-based de novo criterion cannot be assigned here.	cspec PMID:19206169
PS3	Not assessed	Published and curated functional materials were available for review, but no approved functional assay result for p.(Thr241Lys) itself was identified here, so PS3 cannot be assigned on the current evidence.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:19206169 PMID:28404629
PS4	Not assessed	This variant has been reported in ClinVar, including by the ClinGen RASopathy expert panel, but the available evidence does not provide the case counts or PS4 point total needed for the RASopathy point-based enrichment criterion.	clinvar cspec PMID:17704260 PMID:18042262 PMID:19206169
PM1	Met	This missense variant is located in BRAF exon 6, which is explicitly listed by the BRAF RASopathy specification as a critical and well-established functional region for PM1.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy specification requirement that the variant be absent from controls for PM2_Supporting.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this BRAF RASopathy framework.	cspec
PM4	N/A	This is a missense substitution and not a protein length-changing variant, so PM4 does not apply.	cspec
PM5	Met	A different missense change at the same residue, p.(Thr241Pro), is listed as pathogenic/likely pathogenic in the RASopathy VCEP approved functional-study materials, satisfying the BRAF same-codon PM5 rule for one established pathogenic or likely pathogenic residue change.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM6	Not assessed	No assumed de novo report with sufficient case-level detail for this exact variant was identified, so PM6 cannot be assigned from the current evidence.	cspec PMID:19206169
PP1	Not assessed	No segregation data were identified for this exact variant, so co-segregation evidence cannot be counted.	cspec
PP2	Not assessed	The BRAF RASopathy specification allows PP2 when the gnomAD missense z score is greater than 3.09, but a citable gene-level constraint value was not provided in the case materials, so this criterion is left for manual confirmation.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect: REVEL is 0.946, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.468035, and SpliceAI predicts no meaningful splice disruption (max delta score 0.04), supporting a protein-level rather than splice-mediated effect.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in this BRAF RASopathy framework.	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 and does not meet the BRAF RASopathy BA1 stand-alone benign frequency threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD and does not meet the BRAF RASopathy BS1 benign frequency threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals at the point threshold required for BS2.	cspec
BS3	N/A	BS3 is not applicable in this BRAF RASopathy framework.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	This is not a truncating or loss-of-function variant, so the BRAF RASopathy BP1 rule does not apply.	cspec
BP2	Not assessed	No phase or alternate-molecular-explanation data were identified to support BP2.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy framework.	cspec
BP4	Not met	Computational results do not support a benign interpretation for this missense change because REVEL is 0.946, which is above the benign BP4 threshold of 0.3.	cspec revel spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation meeting the point threshold for BP5.	cspec
BP6	N/A	BP6 is not applicable in this BRAF RASopathy framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 does not apply.	cspec spliceai

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