NM_001354609.1:c.2127+3A>G

BRAF · NP_001341538.1:p.? · NM_001354609.1

GRCh37: chr7:140439609 T>C · GRCh38: chr7:140739809 T>C

Gene: BRAF Transcript: NM_001354609.1

Final call

Benign

BA1 stand-alone benign BS1 strong BP4 supporting BP6 supporting benign BP7 supporting

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRAF c.2127+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as benign or likely benign, including a benign expert-panel classification.

This variant is present in population databases at a frequency above the BRAF RASopathy VCEP benign thresholds, with grpmax filtering allele frequencies of 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1.

SpliceAI predicts no significant splice impact for this intronic +3 variant, with a maximum delta score of 0.16, which does not support a deleterious splicing effect and is consistent with BP4 and BP7 in this framework.

Final determination: Rule17 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 Benign.

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 an intronic +3 splice-region change, not a canonical ±1,2 splice-site variant, nonsense variant, or frameshift variant. The BRAF RASopathy VCEP marks PVS1 as not applicable here, and the generic PVS1 scaffold does not support applying PVS1 to this variant class.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to the same amino acid change as a previously established pathogenic variant. This variant is an intronic splice-region change with no defined amino acid substitution, so PS1 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity confirmation was identified for this variant. Available evidence does not provide the point-based de novo data required for PS2 under the RASopathy VCEP framework.	cspec clinvar
PS3	Not assessed	No approved functional or RNA study was identified for this exact variant showing abnormal splicing or another damaging effect. Available evidence is insufficient to apply PS3.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	This variant is reported in ClinVar, but no verified affected-case count, enrichment analysis, or VCEP point total was identified for this exact variant. Available evidence does not support applying PS4.	cspec clinvar
PM1	N/A	PM1 in this BRAF specification is limited to defined protein domains and hotspots. This variant is an intronic splice-region change without a defined amino acid residue in those domains, so PM1 is not applicable.	cspec
PM2	Not met	PM2 requires absence from gnomAD. This variant is present in gnomAD v2.1 at 50/282650 alleles (AF 0.01769%) and in gnomAD v4.1 at 152/1612098 alleles (AF 0.00943%), so it does not meet PM2.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this BRAF RASopathy specification.	cspec
PM4	N/A	PM4 is intended for protein length changes from in-frame insertions/deletions or stop-loss variants. This variant is an intronic splice-region substitution and does not match that variant class.	cspec
PM5	N/A	PM5 applies to a novel missense change at a residue where another pathogenic missense change has been established. This variant is not a missense change, so PM5 is not applicable.	cspec
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant. Available evidence is insufficient to assign PM6 points.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant. Available evidence does not support PP1.	cspec
PP2	N/A	PP2 applies to missense variants in genes with low benign missense variation. This variant is an intronic splice-region variant rather than a missense variant, so PP2 is not applicable.	cspec
PP3	Not met	For splicing impact, PP3 requires computational evidence supporting an abnormal outcome consistent with disease mechanism. SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.16, so available in silico evidence does not support PP3.	cspec spliceai
PP4	N/A	PP4 is not applicable in this BRAF RASopathy specification.	cspec
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BA1	Met	This variant exceeds the BRAF RASopathy VCEP BA1 population threshold of filtering allele frequency at or above 0.05%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant exceeds the BRAF RASopathy VCEP BS1 population threshold of filtering allele frequency at or above 0.025%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	This variant is present in population databases, including one homozygote, but no confirmed unaffected clinical individuals meeting the RASopathy VCEP point-based BS2 framework were identified. Available evidence is insufficient to apply BS2.	cspec gnomad_v2 gnomad_v4
BS3	N/A	BS3 is not applicable in this BRAF RASopathy specification.	cspec
BS4	Not assessed	No segregation data showing lack of cosegregation were identified for this variant. Available evidence is insufficient to apply BS4.	cspec
BP1	N/A	In this VCEP, BP1 is used for truncating or loss-of-function variants in a gain-of-function disease setting when loss of function is not an established disease mechanism. This variant is a noncanonical intronic splice-region change without evidence of a truncating effect, so BP1 is not applicable.	cspec spliceai
BP2	Not assessed	No evidence was identified showing this variant occurring with an alternative molecular explanation in the same gene that would support BP2 point assignment.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy specification.	cspec
BP4	Met	Available computational evidence predicts little or no splice effect. SpliceAI shows a maximum delta score of 0.16, which does not support a meaningful abnormal splicing outcome, so the in silico evidence supports BP4 for a splice-region variant in this VCEP framework.	cspec spliceai
BP5	Not assessed	No evidence was identified showing a different molecular explanation for the phenotype in another gene or a phenotype fully explained by another cause. Available evidence is insufficient to apply BP5.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	Met	This variant is a noncanonical intronic splice-region change at +3, and the BRAF RASopathy VCEP allows BP7 for intronic positions outside canonical splice sites when used with BP4. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.16, which supports BP7.	cspec spliceai

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