Variant: NM_004333.4(BRAF):c.1785T>G (p.Phe595Leu)

CA280058

177672 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 020e6a22-3189-484a-8ca8-77cd1a08adba

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_004333.4:c.1785T>G
NM_004333.4(BRAF):c.1785T>G (p.Phe595Leu)
NC_000007.14:g.140753350A>C
CM000669.2:g.140753350A>C
NC_000007.13:g.140453150A>C
CM000669.1:g.140453150A>C
NC_000007.12:g.140099619A>C
NG_007873.3:g.176415T>G
NM_001354609.1:c.1785T>G
NM_004333.5:c.1785T>G
NR_148928.1:n.2883T>G
ENST00000288602.10:c.1785T>G
ENST00000479537.5:n.69T>G
ENST00000496384.6:n.608T>G
ENST00000497784.1:n.1820T>G

Pathogenic

• Met criteria codes: PM1 PM2 PP3 PP2 PM6_Strong PS4_Supporting

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621). 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). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting.

Met criteria codes

• PM1: Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621).
• PM2: This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6_Strong: The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12).
• PS4_Supporting: The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338) 3 cases - considered patho (1 de novo/no PP16 and 2 no parental DNA) and 2 cases with p.Phe595Ala (1 no parental DNA, 1 unaffected mther tested neg and no father DNA)