Variant: NM_004333.6(BRAF):c.1781A>T (p.Asp594Val)

CA16602425

375946 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 8d88d5d7-5d83-4298-8db6-00da7b7db528

HGVS expressions

NM_004333.6:c.1781A>T
NM_004333.6(BRAF):c.1781A>T (p.Asp594Val)
NC_000007.14:g.140753354T>A
CM000669.2:g.140753354T>A
NC_000007.13:g.140453154T>A
CM000669.1:g.140453154T>A
NC_000007.12:g.140099623T>A
NG_007873.3:g.176411A>T
NM_004333.4:c.1781A>T
NM_001354609.1:c.1781A>T
NM_004333.5:c.1781A>T
NR_148928.1:n.2879A>T
NM_001354609.2:c.1781A>T
NM_001374244.1:c.1901A>T
NM_001374258.1:c.1901A>T
ENST00000288602.10:c.1781A>T
ENST00000479537.5:n.65A>T
ENST00000496384.6:n.604A>T
ENST00000497784.1:n.1816A>T

Pathogenic

• Met criteria codes: PS4_Moderate PS2 PP2 PP3 PM1 PM2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000935844.1, SCV000965957.1, GeneDx internal data). In one proband, the variant was reported as de novo with confirmed parentage (PS2). The c.1781A>T (p.Asp594Val) variant is located in the CR3 activation segment of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the variant may impact protein function (PP3). Finally, c.1781A>T (p.Asp594Val) 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). 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): PS2, PS4_Moderate, PM1, PM2, PP2, PP3,

Met criteria codes

• PS4_Moderate: GeneDx: de novo via WES in a Female with global developmental delay, microcephaly, coarse facial features, and kinky hair One juvenile male with hypotonia, developmental delay, cafe-au-lait macules, curly hair, scarce eyebrows and eyelashes, short nose, full lips, short hands, dry skin (SCV000935844.1) Seen once: antenatal abnormality, hygroma. Craniofacial phenotype typical of CFC, failure to thrive, macrocephaly, curly hair, hypertrophic cardiomyopathy, dry skin, intellectual delay and attention deficit, no speech at age 4. unknown inheritance. (SCV000965957.1)
• PS2: GeneDx internal data
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: REVEL: 0.977
• PM1: CR3 activation segment
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2020-05-18

Published on: 2020-05-21