NM_001354609.1:c.622A>G

BRAF · NP_001341538.1:p.(Ile208Val) · NM_001354609.1

GRCh37: chr7:140507849 T>C · GRCh38: chr7:140808049 T>C

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

BS2 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Ile208Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.622A>G (p.Ile208Val) variant has been reported in ClinVar with mostly likely benign laboratory submissions and an expert-panel uncertain significance classification, and published case-level data describe unaffected carriers and multiple individuals without findings consistent with a RASopathy.

This variant is present in population databases at low frequency, including 4/282526 alleles in gnomAD v2.1 (0.00142%) and 24/1612526 alleles in gnomAD v4.1 (0.00149%), which is below the BRAF RASopathy BS1 threshold of 0.025% and below the BA1 threshold of 0.05%, but means PM2 is not met because the variant is not absent from controls.

No approved variant-specific functional study was identified for p.Ile208Val in the reviewed RASopathy functional-study materials.

Computational evidence does not meet the VCEP missense thresholds: REVEL is 0.318, which is below the PP3 cutoff of 0.7 but above the BP4 cutoff of 0.3, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01; the BayesDel score is -0.174758.

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 and does not fall into the null-variant categories used for PVS1. The BRAF RASopathy specification marks PVS1 as not applicable for this variant context.	cspec pvs1_variant_assessment
PS1	Not assessed	No reviewed source identified a previously established pathogenic variant producing the same amino acid change, so PS1 could not be confirmed from the available evidence.	cspec vcep_raf_alignment
PS2	Not met	Available evidence does not support a confirmed de novo occurrence. In a published report, this variant was detected in an unaffected father, which does not meet the de novo requirement.	cspec PMID:29945942
PS3	Not met	No approved variant-specific functional assay result was identified for p.Ile208Val. The reviewed RASopathy functional-study materials did not show this variant in an approved assay set.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals. Published case-level data instead include unaffected carriers and individuals without findings consistent with a RASopathy.	cspec PMID:29945942 clinvar
PM1	Not met	This variant is in exon 5, while the BRAF RASopathy specification limits PM1 to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627). No hotspot evidence was identified for codon 208.	cspec hotspots
PM2	Not met	This variant is present in population databases and therefore is not absent from controls. In gnomAD v2.1 the total allele frequency is 0.00142% (4/282526), and in gnomAD v4.1 the total allele frequency is 0.00149% (24/1612526).	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this BRAF RASopathy 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	Not assessed	No reviewed source established a pathogenic missense change at this codon or an approved analogous RAF residue that would allow PM5 to be assigned with confidence.	cspec vcep_raf_alignment
PM6	Not met	Available evidence does not support an assumed de novo occurrence. The published prenatal case showed paternal inheritance, which argues against PM6.	cspec PMID:29945942
PP1	Not met	No segregation data were identified showing this variant cosegregates with disease in enough informative meioses to meet PP1.	cspec PMID:29945942
PP2	Not assessed	The BRAF RASopathy specification uses a gnomAD missense Z-score threshold greater than 3.09 for PP2, but that gene-level value was not available in the reviewed materials.	cspec
PP3	Not met	Computational evidence does not meet the BRAF RASopathy PP3 threshold. REVEL is 0.318, which is below the PP3 cutoff of 0.7, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in this BRAF RASopathy framework because phenotype weighting is handled through PS4.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	Population frequency is far below the BA1 threshold. The highest reviewed gnomAD total allele frequency is 0.00149%, which is below the BRAF RASopathy BA1 threshold of 0.05%.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Population frequency is below the BS1 threshold. The highest reviewed gnomAD total allele frequency is 0.00149%, which is below the BRAF RASopathy BS1 threshold of 0.025%.	cspec gnomad_v4 gnomad_v2
BS2	Met	Published case-level evidence describes at least three phenotyped individuals without evidence of a RASopathy who carried this variant, including an unaffected father in the prenatal family. This supports BS2 at a conservative supporting level.	cspec PMID:29945942
BS3	N/A	BS3 is not applicable in this BRAF RASopathy framework.	cspec
BS4	Not met	No formal nonsegregation study was identified that meets the framework requirement for BS4. A single inherited occurrence from a reportedly unaffected parent does not by itself provide a sufficiently documented lack-of-segregation dataset for confident BS4 assignment.	cspec PMID:29945942
BP1	N/A	This is not a truncating or canonical splice variant, so BP1 does not apply under the BRAF RASopathy specification.	cspec
BP2	Not met	No evidence was identified that this variant occurred with an alternative pathogenic RASopathy variant in the same gene in a way that would support BP2.	cspec PMID:29945942
BP3	N/A	BP3 is not applicable in this BRAF RASopathy framework.	cspec
BP4	Not met	Computational evidence does not meet the benign missense threshold because REVEL is 0.318, which is above the BP4 cutoff of 0.3. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but this does not rescue BP4 for this missense variant under the reviewed rule.	cspec revel spliceai bayesdel
BP5	Not met	No alternative molecular explanation in a different gene, and no fully established non-RASopathy diagnosis explaining the reported findings, was identified from the reviewed evidence.	cspec PMID:29945942
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or noncoding variant, so BP7 does not apply.	cspec

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