Mosaic skin disorders - deep sequencing

Gene: BRAF

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 9 Mar 2022, 2:31 p.m. | Last Modified: 9 Mar 2022, 2:31 p.m.

Panel Version: 1.22

Comment on list classification: Promoting this gene from grey to amber but with a recommendation for GREEN rating following GMS review. More than 3 cases with tissue specific mosaic missense variants reported and a relevant skin phenotype.

Created: 23 Nov 2021, 5:02 p.m. | Last Modified: 23 Nov 2021, 5:02 p.m.

Panel Version: 1.12

PMID: 31111470 - Polubothu et al 2020 - Report 7 cases of BRAF c.1799T>A, p.(V600E) variants identified in naevus biopsies from patients with congenital melanocytic naevi (CMN). This represents 7% of the cohort tested for this variant. Sanger sequencing of DNA extracted directly from cultured naevus cells in one patient with mutant BRAF p.(V600E), showed heterozygosity for the BRAF mutation, with an increase in somatic mutation load in comparison with Sanger sequencing of DNA extracted directly from whole tissue from CMN which confirms that the naevus cells are the mutant cells. Immunocytochemistry of primary naevus cells cultured from a BRAF p.(V600E) CMN showed expression of the BRAF variant protein in all naevus cells throughout the cytoplasm.

PMID: 29461977 - Al-Olabi et al 2018 - report 2 patients with sporadic vascular malformations (VMs) and BRAF mutations (Patient 1: NM_004333.4: c.1799T>A;BRAF p.(V600E) - 26% mosaicism in FFPE tissue from VM tissue surgical resection, 0% in blood. Patient 11: NM_002524.4:c.182A>G;BRAF p.(Q61R) - 7% mosaicism in fresh skin biopsy of VM, 0% in blood and saliva). Patient 1 had AVM left face, recurrent bleeding, progressive enlargement and patient 11 had a subtle congenital right foot overgrowth that gradually progressed and extended to buttock by second decade.

Intracranial arteriovenous malformation:
PMID: 31891627 - Goss et al 2019 - report 2 patients with intracranial arteriovenous malformation (AVM) and somatic BRAF mutations [V600E (n = 1), Q636X (n = 1)].

Created: 23 Nov 2021, 4:58 p.m. | Last Modified: 23 Nov 2021, 4:58 p.m.

Panel Version: 1.9

Green List (high evidence)

Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list
Fast track form submitted. Note from Prof Kinsler:
We have noticed that BRAF is not included on this panel. As a key player in mosaic diseases of various types this was an error somehow in the preparation of the original list. Without it's inclusion on the panel various conditions cannot be properly tested for. For example 7% of Congenital Melanocytic Naevus syndrome are caused by BRAF mosaicism and approximately 5% of Arteriovenous Malformations.

Created: 14 Oct 2021, 2:52 p.m. | Last Modified: 14 Oct 2021, 2:53 p.m.

Panel Version: 1.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Melanocytic naevus syndrome (MIM 137550); Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 (MIM 613707); Cardio-facio-cutaneous syndrome 1 (MIM 115150)

Publications

• PMID: 31111470
• 31891627
• 29461977

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments