Variant: NM_004333.6(BRAF):c.1454T>C (p.Leu485Ser)

CA280052

40370 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: b7a354e0-2b3d-4005-bdb1-6de3635711f9

Approved on: 2020-02-27

Published on: 2020-02-27

HGVS expressions

NM_004333.6:c.1454T>C
NM_004333.6(BRAF):c.1454T>C (p.Leu485Ser)
NM_004333.4:c.1454T>C
NM_001354609.1:c.1454T>C
NM_004333.5:c.1454T>C
NR_148928.1:n.1759T>C
NM_001354609.2:c.1454T>C
NM_001374244.1:c.1574T>C
NM_001374258.1:c.1574T>C
ENST00000288602.10:c.1454T>C
ENST00000496384.6:n.277T>C
ENST00000497784.1:n.1489T>C
NC_000007.14:g.140778054A>G
CM000669.2:g.140778054A>G
NC_000007.13:g.140477854A>G
CM000669.1:g.140477854A>G
NC_000007.12:g.140124323A>G
NG_007873.3:g.151711T>C

Likely Pathogenic

• Met criteria codes: PS4_Moderate PP2 PP3 PM5 PM2

• Not Met criteria codes: PS3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1454T>C (p.Leu485Ser) variant in BRAF is absent from gnomAD (PM2). It has been identified in at least 4 patients clinically diagnosed with Cardiofaciocutaneous syndrome (CFC) (PS4_Moderate; 18039235, 21871821, 20395089, SCV000197150.4). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Additionally, computational prediction tools and conservation analysis suggest that p.Leu485Ser may affect the protein (PP3). Two different pathogenic missense variants have been previously identified at this codon of BRAF, each resulting in p.Leu485Phe, which supports that this residue may be critical to the function of the protein (PM5; ClinVar 177844, 13975). A functional assay has been performed on this variant, but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:16474404). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PP2, PP3, PM5.

Met criteria codes

• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: REVEL: 0.956, no predicted splicing impact, evolutionarily conserved
• PM5: ClinVar IDs: 177844, 13975
• PM2: Absent from gnomAD

Not Met criteria codes

• PS3: We examined the effect of the identified mutations on the RAS-ERK pathway by studying the activation of the ELK transcription factor. We transfected expression constructs (KRAS cDNA, NM_004985; BRAF cDNA, NM_00433) with a pFR-luc trans-reporter vector, a pFA2-ELK1 vector and a phRLnull- luc vector in NIH3T3 cells and determined their relative luciferase activity (RLA). We observed a two- to fourfold increase in RLA in cells transfected with two BRAF mutations in cells transfected with two BRAF mutations (L485S and K499E) in the kinase domain. PS3 not counted because it is not an approved assay