Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

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

CA273414

13975 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d7b34568-d590-44cf-a60c-e208532866d3

HGVS expressions

NM_004333.6:c.1455G>C

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

NC_000007.14:g.140778053C>G

CM000669.2:g.140778053C>G

NC_000007.13:g.140477853C>G

CM000669.1:g.140477853C>G

NC_000007.12:g.140124322C>G

NG_007873.3:g.151712G>C

NM_004333.4:c.1455G>C

NM_001354609.1:c.1455G>C

NM_004333.5:c.1455G>C

NR_148928.1:n.1760G>C

NM_001354609.2:c.1455G>C

NM_001374244.1:c.1575G>C

NM_001374258.1:c.1575G>C

ENST00000288602.10:c.1455G>C

ENST00000496384.6:n.278G>C

ENST00000497784.1:n.1490G>C

Pathogenic

PS4_Moderate PS2 PS3 PP2 PP3 PM2

PM5

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1455G>C (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 4 patients with clinical features of a RASopathy, 1 of which was reported as a de novo case with parentage confirmation (PS4_Moderate; PS2; 19206169, 16474404, SCV000197149.4). 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_Moderate, PS2, PS3, PM2, PP2, PP3.

PS4_Moderate

LMM unpublished (SCV000197149.4) + PMID: 16474404

PubMed:16474404

PS2

PubMed:19206169

PS3

PMID 18413255: 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

PP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

REVEL: .757, no predicted splicing impact, evolutionarily conserved

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

ClinVar 40370 (Likely Path)

Approved on: 2020-02-27

Published on: 2020-04-09

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.