Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_004333.6(BRAF):c.1455G>T (p.Leu485Phe)

CA280060

177844 (ClinVar)

Gene: BRAF
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a0d2f8e1-aad3-4fe8-b45c-4e716663a496

HGVS expressions

NM_004333.6:c.1455G>T
NM_004333.6(BRAF):c.1455G>T (p.Leu485Phe)
NM_004333.4:c.1455G>T
NM_001354609.1:c.1455G>T
NM_004333.5:c.1455G>T
NR_148928.1:n.1760G>T
NM_001354609.2:c.1455G>T
NM_001374244.1:c.1575G>T
NM_001374258.1:c.1575G>T
ENST00000288602.10:c.1455G>T
ENST00000496384.6:n.278G>T
ENST00000497784.1:n.1490G>T
NC_000007.14:g.140778053C>A
CM000669.2:g.140778053C>A
NC_000007.13:g.140477853C>A
CM000669.1:g.140477853C>A
NC_000007.12:g.140124322C>A
NG_007873.3:g.151712G>T

Pathogenic

Met criteria codes 6
PM6_Strong PS3 PS4 PP2 PP3 PM2
Not Met criteria codes 1
PM5

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1455G>T (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 5 patients with clinical features of a RASopathy, 2 of which were reported as unconfirmed de novo cases (PS4; PM6_Strong; PMIDs: 18039235, 28524057, SCV000832735.1, SCV000204150.4, SCV000965953.1, Otto-von-Guericke-Universität Magdeburg internal communication). In vitro functional studies provide some evidence that the p.L485F variant may impact protein function (PS3; PMID: 18413255). 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 this variant may affect the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6_Strong, PS3, PM2, PP2, PP3.
Met criteria codes
PM6_Strong
One patient with CFC syndrome, well-phenotyped, assumed de novo without maternity and paternity confirmed (Internal communications with clinician).
PubMed:28524057
PS3
Kinase activities of selected B-Raf missense CFC mutations are compared to known B-Raf mutations found in cancer. Empty vector, wildtype B-Raf (WTB-Raf) or the indicated B-Raf point mutants were transfected in 293Tcells, and B-Raf activity was measured on Flag-immunoprecipitates using a coupled MEK-ERK-MBP phosphorylation assay. L485F showed increased kinase activity compared to WT PubMed:18413255
PS4
PubMed:18039235
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
PM5
Likely Path ClinVar 40370).
Approved on: 2020-02-27
Published on: 2020-02-27
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