Final classification

VUS

PP5PM1PP3PS3

BRAF

c.770A>G

p.Gln257Arg

This variant

The BRAF c.770A>G (p.Gln257Arg) variant has been reported in ClinVar as pathogenic, including expert panel review.

Transcript

NM_001354609.1

HGVS · transcript:coding

NM_001354609.1:c.770A>G

GRCh38

chr7:140801502 T>C

GRCh37

chr7:140501302 T>C

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PP5 supporting, PM1 moderate, PP3 supporting, PS3 moderate; no rule matched the adjudicated criteria.

Classification rationale

PP5PM1PP3PS3 VUS

BRAF c.770A>G

The BRAF c.770A>G (p.Gln257Arg) variant has been reported in ClinVar as pathogenic, including expert panel review.¹ This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,613,978 alleles; AF 0.00006%), which is below the BS1 threshold of 0.025% and the BA1 threshold of 0.05%.² In VCEP-approved functional studies, Q257R showed abnormal results in MEK activation, ERK activation, and BRAF kinase activity assays, consistent with a damaging gain-of-function effect.³ Computational evidence supports a deleterious missense effect, with REVEL 0.838 above the PP3 threshold of 0.7, a positive BayesDel score of 0.476355, and SpliceAI showing only a low predicted splice effect with a maximum delta score of 0.21.⁴

PP5 + PM1 + PP3 + PS3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗

4 revelbayesdelspliceai ↗cspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001354609.1 · variants mapped to exon structure

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

PS3 moderate review Pathogenic

VCEP-approved functional studies show abnormal effects in more than one approved assay for this variant. Q257R is listed as pathogenic in MEK activation, ERK activation, and BRAF kinase activity assays, supporting a damaging gain-of-function effect.

Approved functional studies summary lists BRAF Q257R as pathogenic in MEK activation assay.Approved functional studies summary lists BRAF Q257R as pathogenic in ERK activation assay.Approved functional studies summary lists BRAF Q257R as pathogenic in BRAF kinase activity assay.

cspec ↗

PM1 moderate review Pathogenic

This missense variant is located in exon 6, and the RASopathy expert panel explicitly permits PM1 at moderate strength for variants in exon 6 as a critical and well-established functional region.

Variant maps to exon 6.RASopathy VCEP PM1 includes exon 6 as an eligible region.

cspec ↗

PP3 supporting review Pathogenic

Computational evidence supports a damaging effect. REVEL is 0.838, which is above the PP3 threshold of 0.7, BayesDel is positive at 0.476355, and SpliceAI shows only a low predicted splice effect with a maximum delta score of 0.21, supporting interpretation primarily as a deleterious missense change.

REVEL 0.838 exceeds the PP3 threshold of 0.7.BayesDel score 0.476355 is in the damaging direction.SpliceAI max delta score 0.21 does not provide stronger splice-based evidence than the missense prediction.

cspec ↗spliceai ↗

PP5 supporting review Pathogenic

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.

RASopathy VCEP marks PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PS1 The reviewed evidence did not establish a previously classified pathogenic variant producing the same amino acid change through a different nucleotide change, so this criterion cannot be confirmed from the current record.

PS2 Published reports associated with this variant and cardio-facio-cutaneous syndrome were identified, but the reviewed evidence did not document confirmed maternity and paternity for an exact-variant de novo occurrence, so this criterion cannot be assigned at this time.

PS4 This variant has been reported in affected individuals and is classified as pathogenic in ClinVar, but the reviewed evidence did not establish the exact number of independent affected probands needed to score the RASopathy PS4 point framework.

PM2 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 1/1,613,978 alleles (AF 6.195871319187746e-07; 0.00006%), so it is not absent from controls and does not meet this VCEP PM2 rule.

PM5 Available evidence does not establish a different pathogenic or likely pathogenic missense change at codon 257 in BRAF or RAF1, so this codon-based criterion cannot be confirmed from the reviewed evidence.

PM6 Published reports suggest this variant has been observed in affected individuals, but the reviewed evidence did not provide sufficient patient-level documentation to score an assumed de novo occurrence under the RASopathy point framework.

PP1 No informative meioses showing segregation with disease were identified for this variant.

PP2 This criterion requires a BRAF missense constraint metric above the specified threshold, but the reviewed evidence did not provide the gene-level missense z score needed to confirm the rule.

Benign

BA1 Population frequency is well below the BA1 threshold.

BS1 Population frequency is far below the BS1 threshold.

BS2 No evidence was identified that this variant is observed in healthy individuals in a manner that satisfies the RASopathy point-based BS2 specification.

BS4 No family data showing lack of segregation were identified for this variant.

BP2 No evidence was identified that this variant occurs with an alternative molecular diagnosis in cis or trans in a way that supports this criterion.

BP4 Computational evidence does not support a benign effect.

BP5 No alternate molecular explanation for the phenotype was identified in the reviewed evidence.

N/A · 9 PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19587e-07; MAF= 0.00006%, 1/1613978 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47517e-07; MAF= 0.00008%, 1/1179918 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,978
0 hom

European (non-Finnish)

1 / 1,179,918

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.21). REVEL score = 0.838. BayesDel score = 0.476355.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

4papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous

PMID 16439621 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 moderate

Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.

PMID 16474404 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 moderate

Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles ha

PMID 19376813 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 moderate

Prevalence of class I-III BRAF mutations among 114,662 cancer patients in a larg

PMID 33019809 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 moderate

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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