Variant classification summary

NM_001354609.1:c.1068A>G

BRAF · NP_001341538.1:p.(Gln356=) · NM_001354609.1

GRCh37: chr7:140494180 T>C · GRCh38: chr7:140794380 T>C

Gene: BRAF Transcript: NM_001354609.1

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Gln356=)

gnomAD AF

0.00013939570413416683 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%.

3

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%.

4

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

5

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.

6

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.

7

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.

8

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.

9

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.

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	CSPEC RASopathy VCEP v2.3.0 designates PVS1 as Not Applicable. The variant NM_001354609.1:c.1068A>G is synonymous (NP_001341538.1:p.(Gln356=)) and does not fall into any null-variant category (nonsense, frameshift, canonical splice).	cspec
PS1	Not met	PS1 requires the same amino acid change as a previously established pathogenic variant. This synonymous variant produces no amino acid change (p.Gln356=), so no pathogenic comparator with the same amino acid change exists.	cspec
PS2	Not assessed	No confirmed de novo occurrences (with maternity and paternity confirmation) have been reported in RASopathy patients for this variant. The variant's presence in gnomAD at appreciable frequency with homozygotes makes de novo pathogenicity highly unlikely.	gnomad_v2 gnomad_v4
PS3	Not assessed	No dedicated in vitro functional assay data (e.g., minigene splicing, kinase activity) has been identified for this exact variant. SpliceAI predicts no significant splice impact (max delta 0.01), but this in silico prediction alone does not constitute PS3-level functional evidence.	spliceai
PS4	Not met	The variant is present in gnomAD at population frequencies (v2.1: 0.02546%, 72/282,848 alleles; v4.1: 0.01394%, 225/1,614,110 alleles) that far exceed any plausible enrichment in RASopathy cases. The ClinGen RASopathy VCEP has classified this variant as Benign, confirming no case enrichment.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	PS5 (generic ACMG/AMP 2015) requires a reputable source to have recently reported the variant as pathogenic. ClinVar classifies this variant as Benign after expert panel review by the ClinGen RASopathy VCEP. No reputable source reports it as pathogenic.	clinvar
PM1	Not met	CSPEC RASopathy VCEP restricts PM1 to critical and well-established functional domains: exon 6, exon 11, P-loop (AA 459-474), and CR3 activation segment (AA 594-627). Codon 356 resides in exon 8, outside any of these specified critical domains.	cspec
PM2	Not met	CSPEC RASopathy VCEP requires the variant to be absent from controls (gnomAD) for PM2_Supporting. The variant is present in gnomAD v2.1 (72 alleles, AF 0.02546%) and v4.1 (225 alleles, AF 0.01394%), failing the absence requirement.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. This variant is synonymous (p.Gln356=) and does not alter the amino acid; there is no residue change to compare. PM5 candidates analysis confirms variant class is not missense-like.	cspec pm5_candidates
PM6	Not assessed	No assumed de novo occurrences (without maternity/paternity confirmation) have been reported for this variant in RASopathy probands. The variant's population frequency makes de novo events unlikely.	gnomad_v2 gnomad_v4
PP1	Not assessed	No published multigenerational families demonstrating cosegregation of this variant with RASopathy in multiple affected relatives. Given the variant's population frequency and the VCEP's benign classification, mendelian segregation with disease is unlikely.	gnomad_v2 gnomad_v4 clinvar
PP2	N/A	CSPEC RASopathy VCEP PP2 rule references the missense z-score (>3.09 in gnomAD). This variant is synonymous (p.Gln356=), not a missense variant. The PP2 framework is designed for missense variants and does not apply to synonymous changes.	cspec
PP3	Not met	CSPEC RASopathy VCEP PP3 for missense variants requires REVEL ≥ 0.7. REVEL score is unavailable for this synonymous variant. For splicing impact, SpliceAI delta is 0.01, predicting no significant splice alteration, which does not match a gain-of-function disease mechanism.	spliceai
PP4	N/A	CSPEC RASopathy VCEP v2.3.0 designates PP4 as Not Applicable for this gene-disease pair.	cspec
PP5	N/A	CSPEC RASopathy VCEP v2.3.0 designates PP5 as Not Applicable for this gene-disease pair.	cspec
BA1	Met	The variant has a gnomAD filtering allele frequency (grpmax FAF) of 0.1388% in v2.1 and 0.1350% in v4.1, exceeding the CSPEC RASopathy VCEP BA1 threshold of ≥0.05%. This is consistent with a benign population polymorphism for a dominant RASopathy disorder.	gnomad_v2 gnomad_v4 cspec
BS1	Met	The variant has a gnomAD filtering allele frequency (grpmax FAF) of 0.1388% in v2.1 and 0.1350% in v4.1, exceeding the CSPEC RASopathy VCEP BS1 threshold of ≥0.025%. The observed frequency in the general population is inconsistent with a highly penetrant dominant RASopathy disorder.	gnomad_v2 gnomad_v4 cspec
BS2	Met	Homozygotes for this variant are observed in gnomAD (1 in v2.1, 2 in v4.1). For a dominant disorder such as RASopathy with full penetrance expected at an early age, observation of homozygous healthy individuals in population databases constitutes strong evidence for a benign classification.	gnomad_v2 gnomad_v4
BS3	N/A	CSPEC RASopathy VCEP v2.3.0 designates BS3 as Not Applicable for this gene-disease pair.	cspec
BS4	Not assessed	No published segregation data (lack of cosegregation with disease in affected families) has been identified for this variant. The ClinGen RASopathy VCEP did not apply BS4 in their published benign assessment (citing BA1, BS1, BP4, BP7 instead).	clinvar
BP1	N/A	CSPEC RASopathy VCEP BP1 is intended for truncating (nonsense, frameshift, canonical splice site) variants in genes where the disease mechanism is gain-of-function. This variant is synonymous (p.Gln356=), not a truncating variant.	cspec
BP2	Not assessed	No evidence has been identified of this variant occurring in trans with a known pathogenic BRAF variant in a RASopathy patient. The CSPEC BP2 point-based system requires documented co-occurrence data.
BP4	Met	CSPEC RASopathy VCEP BP4 for splicing variants requires predicted outcome to be negligible or not matching disease mechanism. SpliceAI predicts no significant splice impact for this synonymous variant (max delta score 0.01), satisfying the BP4 criteria for a negligible predicted splicing outcome.	spliceai cspec
BP5	Not assessed	The CSPEC RASopathy VCEP BP5 criterion uses a point-based system. No specific evidence has been identified to support BP5 scoring for this variant.
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	Met	This is a synonymous (silent) variant (p.Gln356=) for which SpliceAI predicts no impact to the splice consensus sequence nor creation of a new splice site (max delta 0.01). The nucleotide is not in a known highly conserved functional element within the critical domains defined by the VCEP. BP7 is applied in conjunction with BP4 per CSPEC guidance.	spliceai cspec

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