Variant: NM_004333.6(BRAF):c.1796C>G (p.Thr599Arg)

CA10603019

280033 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: faecd415-c6bd-4898-b360-35d0ec408f2a

HGVS expressions

NM_004333.6:c.1796C>G
NM_004333.6(BRAF):c.1796C>G (p.Thr599Arg)
NC_000007.14:g.140753339G>C
CM000669.2:g.140753339G>C
NC_000007.13:g.140453139G>C
CM000669.1:g.140453139G>C
NC_000007.12:g.140099608G>C
NG_007873.3:g.176426C>G
NM_004333.4:c.1796C>G
NM_001354609.1:c.1796C>G
NM_004333.5:c.1796C>G
NR_148928.1:n.2894C>G
NM_001354609.2:c.1796C>G
NM_001374244.1:c.1916C>G
NM_001374258.1:c.1916C>G
ENST00000288602.10:c.1796C>G
ENST00000479537.5:n.80C>G
ENST00000496384.6:n.619C>G
ENST00000497784.1:n.1831C>G

Pathogenic

• Met criteria codes: PM2 PM1 PS2_Very Strong PS3 PP2 PS4_Moderate

• Not Met criteria codes: PM5 PP3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1796C>G (p.Thr599Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 3 probands diagnosed with cardiofaciocutaneous syndrome (PS4_Moderate; PMIDs: 19206169, 28650561; Otto-von-Guericke-Universität Magdeburg internal communication). In two of these patients, as well as one proband with phenotypic features suggestive of a RASopathy but no clinical diagnosis, the variant occurred de novo; parentage was confirmed in 2 of these cases (PS2_VS; PMIDs: 19206169, 28650561; GeneDx internal data, SCV000329761.7). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). In vitro functional studies provide some evidence that the p.Thr599Arg variant may impact protein function (PS3; PMID: 19206169). Additionally, the variant is located in BRAF, 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_VeryStrong, PS3, PS4_Moderate, PM1, PM2, PP2.

Met criteria codes

• PM2: Absent from gnomAD.
• PM1: Occurs in the CR3 activation segment (AA 594-627).
• PS2_Very Strong: This variant was observed in 1 proband with CFC syndrome as a de novo occurrence with parentage confirmed (PMID: 19206169) 1 proband with clinical features of a RASopathy but no diagnosis where the variant was de novo with parentage confirmed (GeneDx internal data, SCV000329761.7). 1 proband with CFC syndrome where the variant occurred de novo but parentage was not confirmed (PMID: 28650561)
• PS3: Functional studies performed by Sarkozy et al. 2009 (PMID: 19206169) demonstrate that this variant causes enhanced phosphorylation of MEK and ERK.
• PP2: BRAF is a missense-constrained gene.
• PS4_Moderate: This variant was observed in 3 probands with clinical diagnoses of CFC syndrome (PMID: 19206169, 28650561; Otto-von-Guericke-Universität Magdeburg internal communication).

Not Met criteria codes

• PM5: While pathogenic variants have been observed at this side (ClinVar ID: 40388), PM5 was not applied because PM1 was already met.
• PP3: REVEL score 0.693.

Approved on: 2020-03-24

Published on: 2020-03-24