Variant classification summary

NM_001354609.1:c.1595G>A

BRAF · NP_001341538.1:p.(Cys532Tyr) · NM_001354609.1

GRCh37: chr7:140476811 C>T · GRCh38: chr7:140777011 C>T

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Cys532Tyr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.1595G>A (p.Cys532Tyr, p.C532Y) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Likely pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at supporting strength under the RASopathy VCEP framework.

3

Approved RASopathy VCEP functional assay frameworks are available, but no variant-specific approved functional study result for p.(Cys532Tyr) was identified, so PS3 was not applied.

4

Computational evidence supports a deleterious effect because REVEL is 0.912, above the VCEP PP3 threshold of 0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.00 and BayesDel is 0.376689; these findings support PP3 and do not support BP4.

5

This missense change does not meet PM1 because the RASopathy VCEP limits PM1 in BRAF to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627), and codon 532 is outside the specified amino acid regions.

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 is a missense variant, not a null variant, and the variant-level PVS1 assessment states that it does not fall within the generic PVS1 buckets for nonsense, frameshift, or canonical splice-site changes; therefore PVS1 is not applicable.	pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	No verified evidence was identified showing a different nucleotide change causing the same amino acid substitution as an established pathogenic variant in BRAF or the analogous RAF1 residue, so PS1 was not assessed.	cspec
PS2	Not assessed	No case-level evidence was identified confirming this variant occurred de novo with confirmed maternity and paternity in an affected individual, so PS2 was not assessed.	cspec clinvar
PS3	Not assessed	RASopathy VCEP-approved functional assay frameworks are available, but no variant-specific approved assay result for p.(Cys532Tyr) was identified in the reviewed materials, so PS3 was not applied.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	This variant is reported in ClinVar, but no verified count of unrelated affected individuals or point-based case enrichment data was identified for this variant, so PS4 was not assessed.	cspec clinvar
PM1	Not met	The RASopathy VCEP restricts PM1 for BRAF to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627). This variant affects codon 532, which is outside the specified amino acid regions, so PM1 is not met.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy VCEP requirement that PM2 be applied at supporting strength when the variant is absent from population controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this RASopathy VCEP framework.	cspec
PM4	N/A	This variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable.	cspec
PM5	Not assessed	No verified same-codon pathogenic missense comparator was identified for this residue in the reviewed materials, so PM5 was not assessed.	cspec clinvar
PM6	Not assessed	No case-level evidence was identified showing this variant was assumed de novo without full parental confirmation, so PM6 was not assessed.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	Not assessed	This is a missense variant in BRAF, but no gnomAD missense z score was provided in the reviewed materials to verify that the VCEP threshold of greater than 3.09 is met, so PP2 was not assessed.	cspec
PP3	Met	For this missense variant, the REVEL score is 0.912, which is above the RASopathy VCEP PP3 threshold of 0.7 and supports a deleterious protein effect. SpliceAI shows a maximum delta score of 0.00, arguing against a splice mechanism, and the BayesDel score is 0.376689, which is directionally supportive of a damaging effect.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in this RASopathy VCEP framework, which directs phenotype-weighted case evidence to PS4 instead.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 stand-alone threshold of 0.05%, so BA1 is not met.	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%, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in unaffected adult individuals under the VCEP point-based BS2 framework, so BS2 was not assessed.	cspec
BS3	N/A	BS3 is not applicable in this RASopathy VCEP framework.	cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not assessed.	cspec
BP1	N/A	This criterion is reserved here for truncating variants in genes where gain-of-function missense changes are the primary disease mechanism. Because this variant is missense, BP1 is not applicable.	cspec
BP2	Not assessed	No evidence was identified that this variant occurred with an alternative molecular explanation in the same gene, so BP2 was not assessed.	cspec
BP3	N/A	BP3 is not applicable in this RASopathy VCEP framework.	cspec
BP4	Not met	For this missense variant, the REVEL score is 0.912, which is above the benign BP4 threshold of 0.3, so BP4 is not met. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but the missense predictor threshold for BP4 is not satisfied.	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 variant, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	This is a missense variant rather than a synonymous or relevant noncoding change, so BP7 is not applicable.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.