The variant NM_001354609.1:c.1068A>G (p.Gln356=) is a synonymous substitution in BRAF exon 8, outside the critical functional domains defined by the ClinGen RASopathy VCEP.

This variant is present in gnomAD v2.1 at an allele frequency of 0.02546% (72/282,848 alleles, 1 homozygote) with a grpmax filtering allele frequency of 0.1388%, and in gnomAD v4.1 at 0.01394% (225/1,614,110 alleles, 2 homozygotes) with a grpmax FAF of 0.1350%.

BA1 is met at stand-alone benign strength: the gnomAD grpmax FAF of 0.1388% (v2.1) and 0.1350% (v4.1) exceeds the CSPEC RASopathy VCEP threshold of ≥0.05%.

BS1 is met at strong benign strength: the gnomAD grpmax FAF exceeds the CSPEC RASopathy VCEP threshold of ≥0.025%.

BS2 is met at strong level: homozygous individuals are observed in gnomAD (1 in v2.1, 2 in v4.1), which is inconsistent with a highly penetrant autosomal dominant RASopathy disorder.

BP4 is met at supporting benign strength: SpliceAI predicts no significant splice impact (max delta 0.01), satisfying the VCEP BP4 criterion for negligible predicted splicing outcome.

BP7 is met at supporting benign strength: the variant is synonymous (p.Gln356=) with no predicted splice impact (SpliceAI delta 0.01), applied in conjunction with BP4.

The ClinGen RASopathy Variant Curation Expert Panel has classified this variant as Benign (ClinVar Variation ID 44788), applying criteria BA1, BS1, BP4, and BP7, consistent with this independent assessment.

Under the CSPEC RASopathy VCEP v2.3.0 classification framework Rule 17, BA1 alone (stand-alone benign) is sufficient for a Benign classification. Additionally, BS1 (strong) and BS2 (strong) satisfy Rule 16 (≥2 strong benign criteria). The variant is classified as Benign.