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

CA280060

177844 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: a0d2f8e1-aad3-4fe8-b45c-4e716663a496

Approved on: 2020-02-27

Published on: 2020-02-27

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: PM2 PM6_Strong PS3 PS4 PP2 PP3

• Not Met criteria codes: PM5

Expert Panel

RASopathy VCEP

Criteria Specification Information

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

• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6_Strong: One patient with CFC syndrome, well-phenotyped, assumed de novo without maternity and paternity confirmed (Internal communications with clinician).
• 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

Not Met criteria codes

• PM5: Likely Path ClinVar 40370).