Variant: NM_004333.6(BRAF):c.1024A>G (p.Ile342Val)

CA4516829

359048 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: c21de2c5-2ae3-4535-bcee-ed2d1822a1a7

Approved on: 2020-03-19

Published on: 2020-03-23

HGVS expressions

NM_004333.6:c.1024A>G
NM_004333.6(BRAF):c.1024A>G (p.Ile342Val)
NC_000007.14:g.140794424T>C
CM000669.2:g.140794424T>C
NC_000007.13:g.140494224T>C
CM000669.1:g.140494224T>C
NC_000007.12:g.140140693T>C
NG_007873.3:g.135341A>G
NM_004333.4:c.1024A>G
NM_001354609.1:c.1024A>G
NM_004333.5:c.1024A>G
NR_148928.1:n.1329A>G
NM_001354609.2:c.1024A>G
NM_001374244.1:c.1024A>G
NM_001374258.1:c.1024A>G
ENST00000288602.10:c.1024A>G
ENST00000497784.1:n.1059A>G

Uncertain Significance

• Met criteria codes: PP2

• Not Met criteria codes: BS2 BP4 PP3 PM1 PM2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1024A>G (p.Ile342Val) variant in BRAF has been identified in 0.005644% (2/35438) of Latino chromosomes in gnomAD v2.1.1. This variant has been observed in several individuals whose clinical presentations lacked clear associations with a RASopathy (Invitae internal data, SCV000820707.1; Fulgent internal data; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=8) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data, SCV000617143.2). Computational prediction tools and conservation analyses do not provide strong support for pathogenicity given the disease mechanism. In summary, the clinical significance of this variant is uncertain.

Met criteria codes

• PP2: BRAF is a missense-constrained gene.

Not Met criteria codes

• BS2: GeneDx identified this variant in 8 unaffected parents from 8 different trios, although unclear if they were well phenotyped (SCV000617143.2). However, it was also observed in several individuals whose clinical presentations lacked clear associations with a RASopathy (Invitae internal data, SCV000820707.1; Fulgent internal data; Baylor internal data; Greenwood Genetic Center internal data).
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: REVEL score 0.269. Alamut indicates that this mutation might shift the 3' splice site upstream by 8 nucleotides. No animals in UCSC have valine at this site.
• PM1: Does not occur in exon 6, exon 11, aa 459-474, or aa 594-627.
• PM2: Present in 0.005644% (2/35438) of Latino chromosomes in gnomAD v2; present in 0.007749% (5/64524) of non-Finnish European genomes in gnomAD v3.